Stabilization of phenobarbital sodium for injection

ABSTRACT

The present invention relates to a lyophilized pharmaceutical composition of hydrolytically unstable pharmaceutical compounds, such as phenobarbital or salts thereof. The present invention also relates to an aqueous solution for injection of phenobarbital or salts thereof that is reconstituted from the lyophilized pharmaceutical composition. The pharmaceutical compositions of the present disclosure have an ethanol content in the range from about 5000 ppm to about 70000 ppm. The composition of the present disclosure, in certain embodiments, is stable following two years of storage, wherein the total impurities do not exceed 0.5%. The pharmaceutical compositions of the present disclosure may be used for the treatment of neonatal seizures.

CROSS REFERENCE TO PRIOR APPLICATION

This application claims priority to Indian Patent Application No.202121030559 (filed on Jul. 7, 2021) and U.S. Provisional PatentApplication No. 63/319,918 (filed on Mar. 15, 2022), which are allhereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to a lyophilized pharmaceuticalcomposition of hydrolytically unstable pharmaceutical compounds, such asphenobarbital or salts thereof. The present invention also relates to anaqueous solution for injection of phenobarbital or salts thereof that isreconstituted from the lyophilized pharmaceutical composition. Thepharmaceutical compositions of the present disclosure have an ethanolcontent in the range from about 5000 ppm to about 70000 ppm. Thecomposition of the present disclosure, in certain embodiments, is stablefollowing two years of storage, wherein the total impurities do notexceed 0.5%. The pharmaceutical compositions of the present disclosuremay be used for the treatment of neonatal seizures.

BACKGROUND OF THE INVENTION

Phenobarbital is an anti-epileptic drug which has been used for manyyears in the treatment of neonatal seizures. One of the problemsassociated with a phenobarbital composition, however, is its instabilitydue to hydrolysis, which causes it to possess a higher level ofimpurities. While the compound is freely soluble in water, withsolubility reported to be as high as 333 mg/ml to 1 g/ml, the presenceof hydroxyl ions from the water in the composition results in ahydrolysis pathway that can destroy the phenobarbital ring complex. Thisdestruction results in the possible formation of impurities includingharmful degradants or precipitates.

One known method of improving the stability of phenobarbital sodiuminvolves the use of a lower pH and the use of a mixture of water andgeneric solvents such as alcohol, propylene glycol, glycerin, benzylalcohol, or polyethylene glycol. Currently, marketed compositions ofphenobarbital sodium injections contain benzyl alcohol, alcohol, andpropylene glycol, which pose a higher toxicity risk to neonates andtherefore present a potential safety risk when used in the treatment ofneonatal seizures. Nevertheless, neonatologists have no choice but togive benzyl alcohol-, alcohol-, and propylene glycol-containingcompositions to neonates. The use of a combination of various cosolventsat a higher concentrations also causes a higher osmolality (>500 mOsm)of the product. This is of particular concern for preterm infants, whoare particularly vulnerable to the adverse effects of intravenousadministration of hypertonic substances, as their infusions have beenassociated with increased risk of intraventricular hemorrhage, hepaticnecrosis and necrotizing enterocolitis. Studies have shown thathyperosmolality and metabolic acidosis, then renal dysfunction andfinally acute renal failure and clinical deterioration are major effectsof increasing doses and serum concentrations of propylene glycol inneonates. In addition several case reports of intoxication have pointedout the potential CNS (lethargy, coma, seizures) or local vascularaffects (including hemolysis) most probably associated to higher plasmalevels of propylene glycol and hyperosmolality following acute toxicity.

Propylene glycol is an example of a compound used commercially as adiluent or stabilizer in some extremely hypertonic preparations forintravenous use, including phenytoin, phenobarbital, diazepam, digoxine,and multivitamin solutions. Although it is considered to be a relativelysafe substance, serum hyperosmolality and other harmful effects tonewborns and infants have been reported, including secondary totransdermal absorption of propylene glycol from topical pharmaceuticalpreparations. In addition, the toxicity of propylene glycol to newbornsand infants may be particularly acute because infants and newborns mayhave a delayed development of mechanisms to eliminate propylene glycolfrom their systems. All of these issues with propylene glycol has thusencouraged the search for alternatives to propylene glycol for use as adiluent for substances for intravenous use in neonates.

U.S. Patent Application Publication No. 20210085608 relates tophenobarbital sodium formulations and lyophilization. According to thispublication, lyophilization may result to the stability in aphenobarbital sodium formulation. However, this publication fails todisclose or suggest the role that ethanol may play in the stability of aphenobarbital formulation.

U.S. Pat. No. 9,901,576 relates to phenobarbital formulations. However,the examples of this patent contains higher amount ethanol for thestability. According to regulatory guidelines (for example EuropeanMedicines Agency guidance and The International Council forHarmonisation of Technical Requirements for Pharmaceuticals for HumanUse), the formulations having the solvent amount of over 50000 ppm areunsuitable for use in neonates.

SUMMARY OF THE INVENTION

The present inventors have developed stable pharmaceutical compositionsof the hydrolytically unstable drug phenobarbital or salts thereof. Thepharmaceutical compositions of the present disclosure provides stabilityover a lengthy shelf life, as measured by the amount of total impuritiesformed over time and that does not generate any significant amount ofimpurities during extended storage. The present inventors have alsoobserved that the presence of higher levels of alcohol alone is notsufficient to control the level of impurities. Thus, embodiments of thepresent disclosure relate to the pharmaceutical compositions ofphenobarbital or salts thereof and methods of preparing the same byutilizing a combination of a certain level of alcohol andlyophilization.

In the first aspect, the present disclosure relates to a pharmaceuticalcomposition of phenobarbital or salts thereof that has beenreconstituted from a lyophilized pharmaceutical composition ofphenobarbital or salts thereof, wherein the amount of total impuritiesin the pharmaceutical composition does not exceed 0.2% following 12hours of storage at 20-25° C. or 36 hours of storage at 2-8° C.

In the second aspect, the present disclosure relates to a pharmaceuticalcomposition of phenobarbital or salts thereof, wherein thepharmaceutical composition has an alcohol content in the range fromabout 5000 ppm to 66000 ppm or alternatively from about 5000 ppm to70000 ppm.

In the third aspect, the present disclosure relates to a lyophilizedpharmaceutical composition of phenobarbital or salts thereof, whereinthe composition has an alcohol content in the range from about 5000 ppmto about 66000 ppm or alternatively from about 5000 ppm to about 70000ppm.

In the fourth aspect, the present disclosure relates to a pharmaceuticalcomposition of phenobarbital or salts thereof that has beenreconstituted from a lyophilized pharmaceutical composition ofphenobarbital or salts thereof, wherein the pharmaceutical compositionhas an alcohol content in the range from about 5000 ppm to about 66000ppm or alternatively from about 5000 ppm to about 70000 ppm.

In the fifth aspect, the present disclosure relates to a process ofpreparing the lyophilized pharmaceutical composition of phenobarbital orsalts thereof having an alcohol content in the range from about 5000 ppmto about 66000 ppm or about 70000 ppm, wherein the process comprisesdissolving phenobarbital or salts thereof in water to obtain an aqueoussolution of phenobarbital or salts thereof in a concentration of 10-200mg/ml and lyophilizing the aqueous solution to obtain lyophilizedpharmaceutical composition of phenobarbital or salts thereof.

In the sixth aspect, the present disclosure relates to a process ofpreparing the pharmaceutical composition of phenobarbital or saltsthereof that has been reconstituted from a lyophilized pharmaceuticalcomposition of phenobarbital or salts thereof, wherein thepharmaceutical composition has an alcohol content in the range fromabout 5000 ppm to about 66000 ppm or about 70000 ppm, the processcomprises dissolving phenobarbital or salts thereof in water to obtainan aqueous solution having a concentration 10-200 mg/ml; lyophilizingthe aqueous solution to obtain lyophilized pharmaceutical composition ofphenobarbital or salts thereof; and reconstituting the lyophilizedpharmaceutical composition to obtain the pharmaceutical composition ofphenobarbital or salts thereof.

In the seventh aspect, the present disclosure relates to a lyophilizedpharmaceutical composition of phenobarbital or salts thereof having analcohol content in the range from about 5000 ppm to about 66000 ppm oralternatively from about 5000 ppm to about 70000 ppm, wherein thelyophilized pharmaceutical composition is obtained by a processcomprising: dissolving phenobarbital or salts thereof in water to obtainan aqueous solution having a concentration 10-200 mg/ml and lyophilizingthe aqueous solution to obtain lyophilized pharmaceutical composition ofphenobarbital or salts thereof.

In the eighth aspect, the present disclosure relates to a pharmaceuticalcomposition of phenobarbital or salts thereof that has beenreconstituted from a lyophilized pharmaceutical composition ofphenobarbital or salts thereof having an alcohol content in the rangefrom about 5000 ppm to about 66000 ppm or alternatively from about 5000ppm to about 70000 ppm, wherein the pharmaceutical composition isobtained by a process comprising: dissolving phenobarbital or saltsthereof in water to obtain an aqueous solution having a concentration10-200 mg/ml; lyophilizing the aqueous solution to obtain lyophilizedpharmaceutical composition of phenobarbital or salts thereof; andreconstituting the lyophilized pharmaceutical composition to obtain thepharmaceutical composition of phenobarbital or salts thereof.

In the ninth aspect, the present disclosure relates to a lyophilizedpharmaceutical composition comprising phenobarbital sodium and ethanol,wherein ethanol is present in an amount sufficient to inhibitdegradation of phenobarbital sodium, such that the amount of totalimpurities present following 36 months of storage at 20-25° C. does notexceed 0.2%.

In the tenth aspect, the present disclosure relates to an aqueoussolution for injection comprising phenobarbital sodium and ethanol,wherein ethanol is present in an amount sufficient to inhibitdegradation of phenobarbital sodium, such that the amount of totalimpurities present following 12 hours of storage at 20-25° C. orfollowing 36 hours of storage at 2-8° C. does not exceed 0.2%.

In the eleventh aspect, the present disclosure relates to a process forthe preparation of the pharmaceutical composition of phenobarbital orsalts thereof, wherein the process comprises dissolving phenobarbital orsalt thereof in water to obtain an aqueous solution having aconcentration 10-200 mg/ml and lyophilizing the aqueous solution toobtain lyophilized pharmaceutical composition, wherein phenobarbital orsalts thereof has an alcohol content in the range from about 5000 ppm toabout 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm.

In another aspect, the present disclosure relates to a lyophilizedpharmaceutical composition of phenobarbital sodium, wherein thecomposition has an ethanol content in the range from about 12000 ppm toabout 25000 ppm; wherein the composition is stable up to 36 months ofstorage at 20-25° C. such that the amount of total impurities presentfollowing 36 months of storage at 20-25° C. does not exceed 0.2%; andwherein the composition is free of benzyl alcohol and propylene glycol.

In another aspect, the present disclosure relates to an aqueous solutionfor injection of phenobarbital sodium, wherein the aqueous solution hasan ethanol content in the range from about 12000 ppm to about 25000 ppm;wherein the aqueous solution is stable up to 12 hours of storage at20-25° C. or 36 hours of storage at 2-8° C. such that the amount oftotal impurities present following 12 hours of storage at 20-25° C. orfollowing 36 hours of storage at 2-8° C. does not exceed 0.2%; whereinthe aqueous solution is reconstituted from the lyophilizedpharmaceutical composition of phenobarbital sodium; and wherein theaqueous solution is free of benzyl alcohol and propylene glycol.

In another aspect, the present disclosure relates to a lyophilizedpharmaceutical composition of phenobarbital or salts thereof, whereinthe amount of alcohol in the lyophilized pharmaceutical compositionfollowing 36 months of storage at 20-25° C., is in the range from about5000 ppm to about 66000 ppm or alternatively from about 5000 ppm toabout 70000 ppm.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition of phenobarbital or salts thereof that has beenreconstituted from a lyophilized pharmaceutical composition ofphenobarbital or salts thereof, wherein the amount of alcohol in thepharmaceutical composition following 12 hours of storage at 20-25° C. or36 hours of storage at 2-8° C., is in the range from about 5000 ppm to66000 ppm or alternatively from about 5000 ppm to about 70000 ppm.

In another aspect, the present disclosure relates to a method ofpreventing degradation of phenobarbital or salts thereof, wherein themethod comprises dissolving phenobarbital or salts thereof in water toobtain an aqueous solution having a concentration 10-200 mg/ml; andlyophilizing the aqueous solution to obtain lyophilized pharmaceuticalcomposition of phenobarbital or salts thereof, wherein phenobarbital orsalts thereof has an alcohol content in the range from about 5000 ppm toabout 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The “phenobarbital or salts thereof” that may be used according to thepresent disclosure may be phenobarbital base or a phenobarbital salt.The particular salt form of phenobarbital is not particularly limited,and in non-limiting examples, may be, for example, phenobarbital sodium,phenobarbital potassium, phenobarbital benzathine, phenobarbitalbetaine, or phenobarbital choline. Preferred embodiments utilize aphenobarbital sodium salt.

The term “reconstitution” as used herein, includes the addition ofvehicle/diluent in to the lyophilized phenobarbital lyophilizedphenobarbital. In preferred embodiments, the vehicle/diluent is waterfor injection, an aqueous saline solution or an aqueous dextrosesolution. In additional preferred embodiments, the vehicle/diluent iswater for injection or a 0.9% aqueous saline solution.

The terms “about” as used herein refers to as modifying a term or valuesuch that it is not an absolute. Such terms will be defined by thecircumstances and the terms that they modify as those terms areunderstood by those of skill in the art. This includes, at very least,the degree of expected experimental error, technique error andinstrument error for a given technique used to measure a value. The term“about” when used in the present application preceding a number andreferring to it, is meant to designate any value which lies within therange of ±10%.

The term “total impurities” as used herein, includes known and unknownimpurities, either present from the active pharmaceutical ingredient(API) or generated by the degradation of phenobarbital or salts thereofduring the manufacturing or stability of the pharmaceutical compositionsof the present disclosures. These total impurities includes but notlimited to 2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid, and can be represented by followingstructural formulas:

The term “correctable abnormalities” as used herein is defined as anyabnormality which can be corrected by medication. The correctableabnormalities include hypoglycemia or hypocalcemia.

The term “C₁-C₃ alcohol” as used herein means an alkanol having 1-3carbon atoms which include methanol, ethanol, 1-propanol, or isopropylalcohol.

In the first aspect, the present disclosure relates to a pharmaceuticalcomposition of phenobarbital or salts thereof that has beenreconstituted from a lyophilized pharmaceutical composition ofphenobarbital or salts thereof.

In one embodiment, the pharmaceutical composition of phenobarbital orsalts thereof is an aqueous solution for injection.

In one embodiment, the amount of total impurities in the pharmaceuticalcomposition does not exceed 0.2% following 12 hours of storage at 20-25°C. or 36 hours of storage at 2-8° C.

In one embodiment, the present disclosure relates to a pharmaceuticalcomposition of phenobarbital or salts thereof that has beenreconstituted from a lyophilized pharmaceutical composition ofphenobarbital or salts thereof, wherein the amount of total impuritiesin the pharmaceutical composition does not exceed 0.2% following 12hours of storage at 20-25° C. or 36 hours of storage at 2-8° C.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the lyophilized pharmaceutical composition ofphenobarbital or salts thereof is reconstituted with water forinjection, an aqueous saline or an aqueous dextrose solution. In oneembodiment, the lyophilized pharmaceutical composition of phenobarbitalor salts thereof is reconstituted with 0.9% of aqueous saline.

In one embodiment, phenobarbital or salts thereof is present in aconcentration of 10-200 mg/ml. In one embodiment, phenobarbital or saltsthereof is present in a concentration of 10 mg/ml, 20 mg/ml, 30 mg/ml,40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml,110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml, 150 mg/ml, 160 mg/ml, 170mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the pharmaceutical composition has an alcohol contentin the range from about 5000 ppm to about 66000 ppm or alternativelyfrom about 5000 ppm to about 70000 ppm. In one embodiment, the alcoholcontent is at least about 5000 ppm, about 10000 ppm, about 15000 ppm,about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm,about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm,about 60000 ppm, about 65000 ppm, about 66000 ppm or about 70000 ppm. Inanother embodiment, the alcohol content is in the range from about 12000ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about12000 ppm to about 15000 ppm. In another embodiment, the alcohol contentis in the range from about 15000 ppm to about 70000 ppm, about 15000 ppmto about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 toabout 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm toabout 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppmto about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment the osmolality of said pharmaceutical composition isbelow 500 mOsm/kg. In one embodiment, the osmolality of saidpharmaceutical composition is about 300-400 mOsm/kg.

In one embodiment, the pharmaceutical composition is free of benzylalcohol.

In one embodiment, the pharmaceutical composition is also free ofpropylene glycol.

In a preferred embodiment, the pharmaceutical composition is free ofbenzyl alcohol and propylene glycol.

In another aspect, the present disclosure relates to a method for thetreatment of neonatal seizure in newborn infants in need thereof,comprising administering the pharmaceutical composition of phenobarbitalor salts thereof that has been reconstituted from a lyophilizedpharmaceutical composition of phenobarbital or salts thereof, whereinthe amount of total impurities in the pharmaceutical composition doesnot exceed 0.2% following 12 hours of storage at 20-25° C. or 36 hoursof storage at 2-8° C.

In one embodiment, the newborn infants is of 2 weeks of age or younger.

In one embodiment, the present disclosure relates to a method for thetreatment of neonatal seizure in newborn infants of 2 weeks of age oryounger in need thereof, comprising administering the pharmaceuticalcomposition of phenobarbital or salts thereof that has beenreconstituted from a lyophilized phenobarbital or salts thereof, whereinthe amount of total impurities in the pharmaceutical composition doesnot exceed 0.2% following 12 hours of storage at 20-25° C. or 36 hoursof storage at 2-8° C.

In one embodiment, the method comprises administering the pharmaceuticalcomposition to neonates in whom correctable abnormalities have beenexcluded or corrected. In one embodiment, the said correctableabnormalities are hypoglycemia or hypocalcemia.

In one embodiment, wherein the pharmaceutical composition isadministered intravenously by infusion at a dose of 20 mg/kg over acourse of 15 minutes. In one embodiment, the method comprisesadministration of the pharmaceutical composition at an initial loadingdose of 20 mg/kg over a course of 15 minutes and measuring theelectrographic seizures, wherein if the electrographic seizures persistor recur after completion of the initial loading dose, a second dose 20mg/kg is administered over the subsequent 15 minutes for a total loadingdose of 40 mg/kg.

Electrographic seizures can be measured by any means and instrumentsknown in the art like electroencephalogram (EEG) or using 2-channel EEGwith amplitude-integrated EEG.

In one embodiment, wherein the method for the treatment of neonatalseizure in newborn infants comprising administering the pharmaceuticalcomposition of the first aspect.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the pharmaceutical composition of phenobarbital orsalts thereof is an aqueous solution for injection.

In one embodiment, the lyophilized pharmaceutical composition ofphenobarbital or salts thereof is reconstituted with water forinjection, an aqueous saline or an aqueous dextrose solution. In oneembodiment, the lyophilized pharmaceutical composition of phenobarbitalor salts thereof is reconstituted with 0.9% of aqueous saline.

In one embodiment, phenobarbital or salts thereof is present in aconcentration of 10-200 mg/ml.

In one embodiment, phenobarbital or salts thereof is present in aconcentration of 10 mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml,130 mg/ml, 140 mg/ml, 150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190mg/ml and 200 mg/ml.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the pharmaceutical composition has an alcohol contentin the range from about 5000 ppm to about 66000 ppm or alternativelyfrom about 5000 ppm to about 70000 ppm. In one embodiment, the alcoholcontent is at least about 5000 ppm, about 10000 ppm, about 15000 ppm,about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm,about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm,about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm.In another embodiment, the alcohol content is in the range from about12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm orabout 12000 ppm to about 15000 ppm. In another embodiment, the alcoholcontent is in the range from about 15000 ppm to about 70000 ppm, about15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm orabout 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment the osmolality of said pharmaceutical composition isbelow 500 mOsm/kg. In one embodiment, the osmolality of saidpharmaceutical composition is about 300-400 mOsm/kg.

In one embodiment, the pharmaceutical composition is free of benzylalcohol.

In one embodiment, the pharmaceutical composition is also free ofpropylene glycol.

In a preferred embodiment, the pharmaceutical composition is free ofbenzyl alcohol and propylene glycol.

In the second aspect, the present disclosure relates to a pharmaceuticalcomposition of phenobarbital or salts thereof, wherein thepharmaceutical composition has an alcohol content in the range fromabout 5000 ppm to 66000 ppm or alternatively from about 5000 ppm toabout 70000 ppm.

In one embodiment, the pharmaceutical composition has an alcohol contentin the range from about 5000 ppm to about 66000 ppm or alternativelyfrom about 5000 ppm to about 70000 ppm. In one embodiment, the alcoholcontent is at least about 5000 ppm, about 10000 ppm, about 15000 ppm,about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm,about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm,about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm.In another embodiment, the alcohol content is in the range from about12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm orabout 12000 ppm to about 15000 ppm. In another embodiment, the alcoholcontent is in the range from about 15000 ppm to about 70000 ppm, about15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm orabout 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In another embodiment of the second aspect, the pharmaceuticalcomposition is a lyophilized pharmaceutical composition of phenobarbitalor salts thereof.

In one embodiment, the lyophilized pharmaceutical composition is stableup to 36 months of storage at 20-25° C.

In one embodiment, the amount of total impurities present in thelyophilized pharmaceutical composition following 36 months of storage at20-25° C. does not exceed 0.5%. In one embodiment, the amount of totalimpurities present in the lyophilized pharmaceutical compositionfollowing 36 months of storage at 20-25° C. does not exceed 0.2%.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In another embodiment of the second aspect, the pharmaceuticalcomposition is an aqueous solution for injection of phenobarbital orsalts thereof.

In one embodiment, the aqueous solution is reconstituted from thelyophilized pharmaceutical composition of phenobarbital or saltsthereof. In one embodiment, the lyophilized pharmaceutical compositionis reconstituted with water for injection, an aqueous saline or anaqueous dextrose solution. In another embodiment, the lyophilizedpharmaceutical composition is reconstituted with 0.9% of aqueous saline.

In one embodiment, the aqueous solution comprise phenobarbital or saltsthereof in a concentration of 10-200 mg/ml. In one embodiment,phenobarbital or salts thereof is present in a concentration of 10mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml,150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

In one embodiment, the aqueous solution is stable up to 12 hours ofstorage at 20-25° C.

In one embodiment, the amount of total impurities present in the aqueoussolution following 12 hours of storage at 20-25° C. does not exceed0.5%. In one embodiment, the amount of total impurities present in theaqueous solution following 12 hours of storage at 20-25° C. does notexceed 0.2%.

In one embodiment, the aqueous solution is stable up to 36 hours ofstorage at 2-8° C.

In one embodiment, the amount of total impurities present in the aqueoussolution following 36 hours of storage at 2-8° C. does not exceed 0.5%.In one embodiment, the amount of total impurities present in the aqueoussolution following 36 hours of storage at 2-8° C. does not exceed 0.2%.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the osmolality of said composition is below 500mOsm/kg. In one embodiment, the osmolality of said aqueous solution isabout 300-400 mOsm/kg.

In one embodiment, the pharmaceutical composition is free of benzylalcohol.

In one embodiment, the pharmaceutical composition is also free ofpropylene glycol.

In a preferred embodiment, the pharmaceutical composition is free ofbenzyl alcohol and propylene glycol.

In another aspect, the present disclosure relates to a method for thetreatment of neonatal seizure in newborn infants in need thereof,comprising administering the pharmaceutical composition of phenobarbitalor salts thereof, wherein the pharmaceutical composition has an alcoholcontent in the range from about 5000 ppm to about 66000 ppm oralternatively from about 5000 ppm to about 70000 ppm.

In one embodiment, the newborn infants is 2 weeks of age or younger.

In one embodiment, the present disclosure relates to a method for thetreatment of neonatal seizure in newborn infants of 2 weeks of age oryounger in need thereof, comprising administering the pharmaceuticalcomposition of phenobarbital or salts thereof, wherein thepharmaceutical composition has an alcohol content in the range fromabout 5000 ppm to about 66000 ppm or alternatively from about 5000 ppmto about 70000 ppm.

In one embodiment, the method comprises administering the pharmaceuticalcomposition to neonates in whom correctable abnormalities have beenexcluded or corrected. In one embodiment, the said correctableabnormalities are hypoglycemia or hypocalcemia.

In one embodiment, wherein the pharmaceutical composition of the secondaspect is administered intravenously by infusion at a dose of 20 mg/kgover a course of 15 minutes.

In one embodiment, wherein the method comprises administration of thepharmaceutical composition at an initial loading dose of 20 mg/kg over acourse of 15 minutes and measuring the electrographic seizures, whereinif the electrographic seizures persist or recur after completion of theinitial loading dose, a second dose 20 mg/kg is administered over thesubsequent 15 minutes for a total loading dose of 40 mg/kg.

In one embodiment, wherein the method for the treatment of neonatalseizure in newborn infants comprising administering the pharmaceuticalcomposition of the second aspect.

In one embodiment, the pharmaceutical composition has an alcohol contentin the range from about 5000 ppm to about 66000 ppm or alternativelyfrom about 5000 ppm to about 70000 ppm. In one embodiment, the alcoholcontent is at least about 5000 ppm, about 10000 ppm, about 15000 ppm,about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm,about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm,about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm.In another embodiment, the alcohol content is in the range from about12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm orabout 12000 ppm to about 15000 ppm. In another embodiment, the alcoholcontent is in the range from about 15000 ppm to about 70000 ppm, about15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm orabout 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the pharmaceutical composition is free of benzylalcohol.

In one embodiment, the pharmaceutical composition is also free ofpropylene glycol.

In a preferred embodiment, the pharmaceutical composition is free ofbenzyl alcohol and propylene glycol.

In another embodiment, the pharmaceutical composition is a lyophilizedpharmaceutical composition of phenobarbital or salts thereof.

In one embodiment, the lyophilized pharmaceutical composition is stableup to 36 months of storage at 20-25° C.

In one embodiment, the amount of total impurities present in thelyophilized pharmaceutical composition following 36 months of storage at20-25° C. does not exceed 0.5%. In one embodiment, the amount of totalimpurities present in the lyophilized pharmaceutical compositionfollowing 36 months of storage at 20-25° C. does not exceed 0.2%.

In another embodiment, the pharmaceutical composition is an aqueoussolution for injection of phenobarbital or salts thereof.

In one embodiment, the aqueous solution is reconstituted from thelyophilized pharmaceutical composition of phenobarbital or saltsthereof. In one embodiment, the lyophilized pharmaceutical compositionis reconstituted with water for injection, an aqueous saline or anaqueous dextrose solution. In another embodiment, the lyophilizedpharmaceutical composition is reconstituted with 0.9% of aqueous saline.

In one embodiment, the aqueous solution comprise phenobarbital or saltsthereof in a concentration of 10-200 mg/ml. In one embodiment,phenobarbital or salts thereof is present in a concentration of 10mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml,150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

In one embodiment, the aqueous solution is stable up to 12 hours ofstorage at 20-25° C.

In one embodiment, the amount of total impurities present in the aqueoussolution following 12 hours of storage at 20-25° C. does not exceed0.5%. In one embodiment, the amount of total impurities present in theaqueous solution following 12 hours of storage at 20-25° C. does notexceed 0.2%.

In one embodiment, the aqueous solution is stable up to 36 hours ofstorage at 2-8° C.

In one embodiment, the amount of total impurities present in the aqueoussolution following 36 hours of storage at 2-8° C. does not exceed 0.5%.In one embodiment, the amount of total impurities present in the aqueoussolution following 36 hours of storage at 2-8° C. does not exceed 0.2%.

In one embodiment, the osmolality of said composition is below 500mOsm/kg. In one embodiment, the osmolality of said aqueous solution isabout 300-400 mOsm/kg.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In the third aspect, the present disclosure relates to a lyophilizedpharmaceutical composition of phenobarbital or salts thereof, whereinthe composition has an alcohol content in the range from about 5000 ppmto about 66000 ppm or alternatively from about 5000 ppm to about 70000ppm.

In one embodiment, the lyophilized pharmaceutical composition has analcohol content in the range from about 5000 ppm to about 66000 ppm oralternatively from about 5000 ppm to about 70000 ppm. In one embodiment,the alcohol content is at least about 5000 ppm, about 10000 ppm, about15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about70000 ppm. In another embodiment, the alcohol content is in the rangefrom about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000ppm or about 12000 ppm to about 15000 ppm. In another embodiment, thealcohol content is in the range from about 15000 ppm to about 70000 ppm,about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm,about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm,about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppmor about 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the lyophilized pharmaceutical composition is stableup to 36 months of storage at 20-25° C.

In one embodiment, the amount of total impurities present in thelyophilized pharmaceutical composition following 36 months of storage at20-25° C. does not exceed 0.5%. In one embodiment, the amount of totalimpurities present in the lyophilized pharmaceutical compositionfollowing 36 months of storage at 20-25° C. does not exceed 0.2%.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the lyophilized pharmaceutical composition is free ofbenzyl alcohol.

In one embodiment, the lyophilized pharmaceutical composition is alsofree of propylene glycol.

In a preferred embodiment, the lyophilized pharmaceutical composition isfree of benzyl alcohol and propylene glycol.

In another aspect, the present disclosure relates to a method for thetreatment of neonatal seizure in newborn infants in need thereof,comprising administering the lyophilized pharmaceutical composition ofphenobarbital or salts thereof, and wherein the lyophilizedpharmaceutical composition has an alcohol content in the range fromabout 5000 ppm to about 66000 ppm.

In one embodiment, the newborn infants is of 2 weeks of age or younger.

In one embodiment, the present disclosure relates to a method for thetreatment of neonatal seizure in newborn infants of 2 weeks of age oryounger in need thereof, comprising administering the lyophilizedpharmaceutical composition of phenobarbital or salts thereof, andwherein the lyophilized pharmaceutical composition has an alcoholcontent in the range from about 5000 ppm to about 66000 ppm.

In one embodiment, the method comprises reconstituting the lyophilizedpharmaceutical composition of phenobarbital or salts thereof immediatelyprior to the administration.

In one embodiment, the lyophilized pharmaceutical composition isreconstituted with water for injection, an aqueous saline or an aqueousdextrose solution to obtain the aqueous solution for injection ofphenobarbital or salts thereof.

In one embodiment, the method comprises administering the aqueoussolution to neonates in whom correctable abnormalities have beenexcluded or corrected. In one embodiment, the said correctableabnormalities are hypoglycemia or hypocalcemia.

In one embodiment, wherein the aqueous solution is administeredintravenously by infusion at a dose of 20 mg/kg over a course of 15minutes.

In one embodiment, wherein the method comprises administration of theaqueous solution at an initial loading dose of 20 mg/kg over a course of15 minutes and measuring the electrographic seizures, wherein if theelectrographic seizures persist or recur after completion of the initialloading dose, a second dose 20 mg/kg is administered over the subsequent15 minutes for a total loading dose of 40 mg/kg.

In one embodiment, wherein the method for the treatment of neonatalseizure in newborn infants comprising administering the lyophilizedpharmaceutical composition of the third aspect.

In one embodiment, the lyophilized pharmaceutical composition has analcohol content in the range from about 5000 ppm to about 66000 ppm oralternatively from about 5000 ppm to about 70000 ppm. In one embodiment,the alcohol content is at least about 5000 ppm, about 10000 ppm, about15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm, about55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, or about70000 ppm. In another embodiment, the alcohol content is in the rangefrom about 12000 ppm to about 70000 ppm, about 12000 ppm to about 66000ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about 60000ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about 50000ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about 40000ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about 30000ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about 20000ppm or about 12000 ppm to about 15000 ppm. In another embodiment, thealcohol content is in the range from about 15000 ppm to about 70000 ppm,about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm,about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm,about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppmor about 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the lyophilized pharmaceutical composition is stableup to 36 months of storage at 20-25° C.

In one embodiment, the amount of total impurities present in thelyophilized pharmaceutical composition following 36 months of storage at20-25° C. does not exceed 0.5%. In one embodiment, the amount of totalimpurities present in the lyophilized pharmaceutical compositionfollowing 36 months of storage at 20-25° C. does not exceed 0.2%.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the lyophilized pharmaceutical composition is free ofbenzyl alcohol.

In one embodiment, the lyophilized pharmaceutical composition is alsofree of propylene glycol.

In a preferred embodiment, the lyophilized pharmaceutical composition isfree of benzyl alcohol and propylene glycol.

In the fourth aspect, the present disclosure relates to a pharmaceuticalcomposition of phenobarbital or salts thereof that has beenreconstituted from a lyophilized pharmaceutical composition ofphenobarbital or salts thereof, wherein the pharmaceutical compositionhas an alcohol content in the range from about 5000 ppm to about 66000ppm or alternatively from about 5000 ppm to about 70000 ppm.

In one embodiment, the pharmaceutical composition has an alcohol contentin the range from about 5000 ppm to about 66000 ppm or alternativelyfrom about 5000 ppm to about 70000 ppm. In one embodiment, the alcoholcontent is at least about 5000 ppm, about 10000 ppm, about 15000 ppm,about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm,about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm,about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm.In another embodiment, the alcohol content is in the range from about12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm orabout 12000 ppm to about 15000 ppm. In another embodiment, the alcoholcontent is in the range from about 15000 ppm to about 70000 ppm, about15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm orabout 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the lyophilized pharmaceutical composition isreconstituted with water for injection, an aqueous saline or an aqueousdextrose solution. In one embodiment, the lyophilized pharmaceuticalcomposition is reconstituted with 0.9% aqueous saline.

In one embodiment, the pharmaceutical composition is an aqueous solutionfor injection of phenobarbital or salts thereof.

In one embodiment, the pharmaceutical composition comprise phenobarbitalor salts thereof in a concentration of 10-200 mg/ml. In one embodiment,phenobarbital or salts thereof is present in a concentration of 10mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml,150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

In one embodiment, the pharmaceutical composition is stable up to 12hours of storage at 20-25° C.

In one embodiment, the amount of total impurities present in thepharmaceutical composition following 12 hours of storage at 20-25° C.does not exceed 0.5%. In one embodiment, the amount of total impuritiespresent in the pharmaceutical composition following 12 hours of storageat 20-25° C. does not exceed 0.2%.

In one embodiment, the pharmaceutical composition is stable up to 36hours of storage at 2-8° C.

In one embodiment, the amount of total impurities present in thepharmaceutical composition following 36 hours of storage at 2-8° C. doesnot exceed 0.5%. In one embodiment, the amount of total impuritiespresent in the pharmaceutical composition following 36 hours of storageat 2-8° C. does not exceed 0.2%.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the osmolality of said pharmaceutical composition isbelow 500 mOsm/kg. In one embodiment, the osmolality of said aqueoussolution is about 300-400 mOsm/kg.

In one embodiment, the pharmaceutical composition is free of benzylalcohol.

In one embodiment, the pharmaceutical composition is also free ofpropylene glycol.

In a preferred embodiment, the pharmaceutical composition is free ofbenzyl alcohol and propylene glycol.

In another aspect, the present disclosure relates to a method for thetreatment of neonatal seizure in newborn infants in need thereof,comprising administering the pharmaceutical composition of phenobarbitalor salts thereof that has been reconstituted from a lyophilizedpharmaceutical composition of phenobarbital or salts thereof, andwherein the pharmaceutical composition has an alcohol content in therange from about 5000 ppm to about 66000 ppm or alternatively from about5000 ppm to about 70000 ppm.

In one embodiment, the newborn infants is of 2 weeks of age or younger.

In one embodiment, the present disclosure relates to a method for thetreatment of neonatal seizure in newborn infants of 2 weeks of age oryounger in need thereof, comprising administering the pharmaceuticalcomposition of phenobarbital or salts thereof that has beenreconstituted from a lyophilized pharmaceutical composition ofphenobarbital or salts thereof, and wherein the pharmaceuticalcomposition has an alcohol content in the range from about 5000 ppm toabout 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm.

In one embodiment, the method comprises administering the pharmaceuticalcomposition to neonates in whom correctable abnormalities have beenexcluded or corrected. In one embodiment, the said correctableabnormalities are hypoglycemia or hypocalcemia.

In one embodiment, wherein the pharmaceutical composition isadministered intravenously by infusion at a dose of 20 mg/kg over acourse of 15 minutes.

In one embodiment, wherein the method comprises administration of thepharmaceutical composition at an initial loading dose of 20 mg/kg over acourse of 15 minutes and measuring the electrographic seizures, whereinif the electrographic seizures persist or recur after completion of theinitial loading dose, a second dose 20 mg/kg is administered over thesubsequent 15 minutes for a total loading dose of 40 mg/kg.

In one embodiment, wherein the method for the treatment of neonatalseizure in newborn infants comprising administering the pharmaceuticalcomposition of the fourth aspect.

In one embodiment, the pharmaceutical composition has an alcohol contentin the range from about 5000 ppm to about 66000 ppm or alternativelyfrom about 5000 ppm to about 70000 ppm. In one embodiment, the alcoholcontent is at least about 5000 ppm, about 10000 ppm, about 15000 ppm,about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm,about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm,about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm.In another embodiment, the alcohol content is in the range from about12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm orabout 12000 ppm to about 15000 ppm. In another embodiment, the alcoholcontent is in the range from about 15000 ppm to about 70000 ppm, about15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm orabout 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the lyophilized pharmaceutical composition isreconstituted with water for injection, an aqueous saline or an aqueousdextrose solution. In one embodiment, the lyophilized pharmaceuticalcomposition is reconstituted with 0.9% aqueous saline.

In one embodiment, the pharmaceutical composition is an aqueous solutionfor injection of phenobarbital or salts thereof.

In one embodiment, the pharmaceutical composition comprise phenobarbitalor salts thereof in a concentration of 10-200 mg/ml. In one embodiment,phenobarbital or salts thereof is present in a concentration of 10mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml,150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

In one embodiment, the pharmaceutical composition is stable up to 12hours of storage at 20-25° C.

In one embodiment, the amount of total impurities present in thepharmaceutical composition following 12 hours of storage at 20-25° C.does not exceed 0.5%. In one embodiment, the amount of total impuritiespresent in the pharmaceutical composition following 12 hours of storageat 20-25° C. does not exceed 0.2%.

In one embodiment, the pharmaceutical composition is stable up to 36hours of storage at 2-8° C.

In one embodiment, the amount of total impurities present in thepharmaceutical composition following 36 hours of storage at 2-8° C. doesnot exceed 0.5%. In one embodiment, the amount of total impuritiespresent in the pharmaceutical composition following 36 hours of storageat 2-8° C. does not exceed 0.2%.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the osmolality of the pharmaceutical composition isbelow 500 mOsm/kg. In one embodiment, the osmolality of thepharmaceutical composition is about 300-400 mOsm/kg.

In one embodiment, the pharmaceutical composition is free of benzylalcohol.

In one embodiment, the pharmaceutical composition is also free ofpropylene glycol.

In a preferred embodiment, the pharmaceutical composition is free ofbenzyl alcohol and propylene glycol.

In the fifth aspect, the present disclosure relates to a process ofpreparing the lyophilized pharmaceutical composition of phenobarbital orsalts thereof having an alcohol content in the range from about 5000 ppmto about 66000 ppm or alternatively from about 5000 ppm to about 70000ppm, wherein the process comprises dissolving phenobarbital or saltsthereof in water to obtain an aqueous solution of phenobarbital or saltsthereof in a concentration of 10-200 mg/ml and lyophilizing the aqueoussolution to obtain lyophilized pharmaceutical composition ofphenobarbital or salts thereof.

In one embodiment, the process comprises measuring the alcohol contentof an aqueous solution of phenobarbital or salts thereof. In oneembodiment, if the alcohol content of the aqueous solution is below 5000ppm then the process further comprises a step of adding an alcohol in aquantity that is sufficient to achieve the alcohol content of at leastabout 5000 ppm.

In one embodiment, the process comprises measuring the alcohol contentof the lyophilized pharmaceutical composition of phenobarbital or saltsthereof. In one embodiment, the process may comprises repeating steps oflyophilization to achieve the alcohol content not more than about 66000ppm or about 70000 ppm. In one embodiment, if the alcohol content isabove 66000 ppm or 70000 ppm (whichever is desired), the process furthercomprises repeating the lyophilization step till the alcohol content ofthe lyophilized pharmaceutical composition is not more than about 66000ppm or not more than about 70000 ppm. It is understood that even asingle additional cycle of lyophilization would be sufficient or it hasto be repeated n number of times to obtain the desired alcohol level.

In another aspect, the present disclosure relates to a process ofpreparing the lyophilized pharmaceutical composition of phenobarbital orsalts thereof having an alcohol content in the range from about 5000 ppmto about 66000 ppm or alternatively from about 5000 ppm to about 70000ppm, wherein the process comprises dissolving phenobarbital or saltsthereof in water to obtain an aqueous solution having a concentration10-200 mg/ml; measuring the alcohol content of aqueous solution; if thealcohol content is below 5000 ppm, adding an alcohol to achieve thealcohol content of at least about 5000 ppm; lyophilizing the aqueoussolution to obtain lyophilized pharmaceutical composition; measuring thealcohol content of the lyophilized pharmaceutical composition; if thealcohol content is above 66000 ppm or above about 70000 ppm (whicheveris desired), repeating the lyophilization step multiple times till thealcohol content of the lyophilized pharmaceutical composition is notmore than about 66000 ppm or is not more than about 70000 ppm.

In one embodiment, the process comprises addition of a pH modifier tothe aqueous solution of phenobarbital or salts thereof to achieve a pHin a range of 8-12, preferably in a range of 9-11, more preferably in arange of 9-10.5.

In one embodiment, the pH modifier is selected from HCl and/or NaOH. Inone embodiment, the pH modifier is aqueous HCl solution.

In one embodiment, the lyophilized pharmaceutical composition is stableup to 36 months of storage at 20-25° C.

In one embodiment, the lyophilized pharmaceutical composition has analcohol content of at least about 5000 ppm, about 10000 ppm, about 15000ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm,about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm,about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm.In another embodiment, the alcohol content is in the range from about12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm orabout 12000 ppm to about 15000 ppm. In another embodiment, the alcoholcontent is in the range from about 15000 ppm to about 70000 ppm, about15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm orabout 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the lyophilized pharmaceutical composition is stableup to 36 months of storage at 20-25° C.

In one embodiment, the amount of total impurities present in thelyophilized pharmaceutical composition following 36 months of storage at20-25° C. does not exceed 0.5%. In one embodiment, the amount of totalimpurities present in the lyophilized pharmaceutical compositionfollowing 36 months of storage at 20-25° C. does not exceed 0.2%.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the lyophilized pharmaceutical composition is free ofbenzyl alcohol.

In one embodiment, the lyophilized pharmaceutical composition is alsofree of propylene glycol.

In a preferred embodiment, the lyophilized pharmaceutical composition isfree of benzyl alcohol and propylene glycol.

In the sixth aspect, the present disclosure relates to a process ofpreparing the pharmaceutical composition of phenobarbital or saltsthereof that has been reconstituted from a lyophilized pharmaceuticalcomposition of phenobarbital or salts thereof, wherein thepharmaceutical composition has an alcohol content in the range fromabout 5000 ppm to about 66000 ppm or alternatively from about 5000 ppmto about 70000 ppm, wherein the process comprises dissolvingphenobarbital or salts thereof in water to obtain an aqueous solutionhaving a concentration 10-200 mg/ml; lyophilizing the aqueous solutionto obtain lyophilized pharmaceutical composition of phenobarbital orsalts thereof; and reconstituting the lyophilized pharmaceuticalcomposition to obtain the pharmaceutical composition of phenobarbital orsalts thereof.

In one embodiment, the process comprises measuring the alcohol contentof an aqueous solution of phenobarbital or salts thereof. In oneembodiment, if the alcohol content of the aqueous solution is below 5000ppm then the process further comprises a step of adding an alcohol in aquantity that is sufficient to achieve the alcohol content of at leastabout 5000 ppm.

In one embodiment, the process comprises measuring the alcohol contentof the lyophilized pharmaceutical composition of phenobarbital or saltsthereof. In one embodiment, the process may comprises additional stepsof lyophilization to achieve the alcohol content not more than about66000 ppm or not more than about 70000 ppm (whichever is desired). Inone embodiment, if the alcohol content is above 66000 ppm or about 70000ppm, the process further comprises repeating the lyophilization steptill the alcohol content of the lyophilized pharmaceutical compositionis not more than about 66000 ppm or not more than about 70000 ppm. It isunderstood that even a single additional cycle of lyophilization wouldbe sufficient or it has to be repeated n number of times to obtain thedesired alcohol level.

In another aspect, the present disclosure relates to a process ofpreparing the pharmaceutical composition of phenobarbital or saltsthereof that has been reconstituted from a lyophilized pharmaceuticalcomposition of phenobarbital or salts thereof, wherein thepharmaceutical composition has an alcohol content in the range fromabout 5000 ppm to about 66000 ppm or alternatively from about 5000 ppmto about 70000 ppm, wherein the process comprises dissolvingphenobarbital or salts thereof in water to obtain an aqueous solutionhaving a concentration 10-200 mg/ml; measuring the alcohol content ofaqueous solution; if the alcohol content is below 5000 ppm, adding analcohol to achieve the alcohol content of at least about 5000 ppm;lyophilizing the aqueous solution to obtain lyophilized pharmaceuticalcomposition; measuring the alcohol content of the lyophilizedpharmaceutical composition; if the alcohol content is above 66000 ppm orabout 70000 ppm (whichever is desired), repeating the lyophilizationstep multiple times till the alcohol content of the lyophilizedpharmaceutical composition is not more than about 66000 ppm or not morethan about 70000 ppm (whichever is desired); and reconstituting thelyophilized pharmaceutical composition to obtain the pharmaceuticalcomposition of phenobarbital or salts thereof.

In one embodiment, the process comprises addition of a pH modifier tothe aqueous solution of phenobarbital or salts thereof to achieve a pHin a range of 8-12, preferably in a range of 9-11, more preferably in arange of 9-10.5. In one embodiment, the pH modifier is selected from HCland/or NaOH. In one embodiment, the pH modifier is aqueous HCl solution.

In one embodiment, the lyophilized pharmaceutical composition isreconstituted with water for injection, an aqueous saline or an aqueousdextrose solution. In one embodiment, the lyophilized pharmaceuticalcomposition is reconstituted with 0.9% aqueous saline.

In one embodiment, the pharmaceutical composition has an alcohol contentin the range from about 5000 ppm to about 66000 ppm or alternativelyfrom about 5000 ppm to about 70000 ppm. In one embodiment, the alcoholcontent is at least about 5000 ppm, about 10000 ppm, about 15000 ppm,about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm,about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm,about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm.In another embodiment, the alcohol content is in the range from about12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm orabout 12000 ppm to about 15000 ppm. In another embodiment, the alcoholcontent is in the range from about 15000 ppm to about 70000 ppm, about15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm orabout 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the pharmaceutical composition is an aqueous solutionfor injection of phenobarbital or salts thereof.

In one embodiment, the pharmaceutical composition comprise phenobarbitalor salts thereof in a concentration of 10-200 mg/ml. In one embodiment,phenobarbital or salts thereof is present in a concentration of 10mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml,150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

In one embodiment, the pharmaceutical composition is stable up to 12hours of storage at 20-25° C.

In one embodiment, the amount of total impurities in the pharmaceuticalcomposition present following 12 hours of storage at 20-25° C. does notexceed 0.5%. In one embodiment, the amount of total impurities presentin the pharmaceutical composition following 12 hours of storage at20-25° C. does not exceed 0.2%.

In one embodiment, the pharmaceutical composition is stable up to 36hours of storage at 2-8° C.

In one embodiment, the amount of total impurities present in thepharmaceutical composition following 36 hours of storage at 2-8° C. doesnot exceed 0.5%. In one embodiment, the amount of total impuritiespresent in the pharmaceutical composition following 36 hours of storageat 2-8° C. does not exceed 0.2%.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the osmolality of the pharmaceutical composition isbelow 500 mOsm/kg. In one embodiment, the osmolality of thepharmaceutical composition is about 300-400 mOsm/kg.

In one embodiment, the pharmaceutical composition is free of benzylalcohol.

In one embodiment, the pharmaceutical composition is also free ofpropylene glycol.

In a preferred embodiment, the pharmaceutical composition is free ofbenzyl alcohol and propylene glycol.

In the seventh aspect, the present disclosure relates to a lyophilizedpharmaceutical composition of phenobarbital or salts thereof having analcohol content in the range from about 5000 ppm to about 66000 ppm oralternatively from about 5000 ppm to about 70000 ppm, wherein thelyophilized pharmaceutical composition is obtained by a processcomprising: dissolving phenobarbital or salts thereof in water to obtainan aqueous solution having a concentration 10-200 mg/ml and lyophilizingthe aqueous solution to obtain lyophilized pharmaceutical composition ofphenobarbital or salts thereof.

In one embodiment, the process comprises measuring the alcohol contentof an aqueous solution of phenobarbital or salts thereof. In oneembodiment, if the alcohol content of the aqueous solution is below 5000ppm then the process further comprises a step of adding an alcohol in aquantity that is sufficient to achieve the alcohol content of at leastabout 5000 ppm.

In one embodiment, the process comprises measuring the alcohol contentof the lyophilized pharmaceutical composition of phenobarbital or saltsthereof. In one embodiment, the process may comprises an additional stepof lyophilization to achieve the alcohol content not more than about66000 ppm or not more than 70000 ppm (whichever is desired). In oneembodiment, if the alcohol content is above 66000 ppm or about 70000ppm, the process further comprises repeating the lyophilization steptill the alcohol content of the lyophilized pharmaceutical compositionis not more than about 66000 ppm or not more than about 70000 ppm(whichever is desired). It is understood that even a single additionalcycle of lyophilization would be sufficient or it has to be repeated nnumber of times to obtain the desired alcohol level.

In one embodiment, the process comprises addition of a pH modifier tothe aqueous solution of phenobarbital or salts thereof to achieve a pHin a range of 8-12, preferably in a range of 9-11, more preferably in arange of 9-10.5.

In one embodiment, the pH modifier is selected from HCl and/or NaOH. Inone embodiment, the pH modifier is aqueous HCl solution.

In one embodiment, the lyophilized pharmaceutical composition has analcohol content of at least about 5000 ppm, about 10000 ppm, about 15000ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm,about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm,about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm.In another embodiment, the alcohol content is in the range from about12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm orabout 12000 ppm to about 15000 ppm. In another embodiment, the alcoholcontent is in the range from about 15000 ppm to about 70000 ppm, about15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm orabout 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the lyophilized pharmaceutical composition is stableup to 36 months of storage at 20-25° C.

In one embodiment, the amount of total impurities present in thelyophilized pharmaceutical composition following 36 months of storage at20-25° C. does not exceed 0.5%. In one embodiment, the amount of totalimpurities present in the lyophilized pharmaceutical compositionfollowing 36 months of storage at 20-25° C. does not exceed 0.2%.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the lyophilized pharmaceutical composition is free ofbenzyl alcohol.

In one embodiment, the lyophilized pharmaceutical composition is alsofree of propylene glycol.

In a preferred embodiment, the lyophilized pharmaceutical composition isfree of benzyl alcohol and propylene glycol.

In order to achieve a desired stability, the lyophilized pharmaceuticalcomposition should have an alcohol content in the range from about 5000ppm to 66000 ppm or alternatively from about 5000 ppm to about 70000ppm, and thus the process may include the steps as discussed above formeasuring the alcohol content, adding alcohol or removing additionalalcohol by repeating the lyophilization step and ensuring that thealcohol content is achieved as described above.

In the eight aspect, the present disclosure relates to a pharmaceuticalcomposition of phenobarbital or salts thereof that has beenreconstituted from a lyophilized pharmaceutical composition ofphenobarbital or salts thereof having an alcohol content in the rangefrom about 5000 ppm to about 66000 ppm or alternatively from about 5000ppm to about 70000 ppm, wherein the pharmaceutical composition isobtained by a process comprising: dissolving phenobarbital or saltsthereof in water to obtain an aqueous solution having a concentration10-200 mg/ml; lyophilizing the aqueous solution to obtain lyophilizedpharmaceutical composition of phenobarbital or salts thereof; andreconstituting the lyophilized pharmaceutical composition to obtain thepharmaceutical composition of phenobarbital or salts thereof.

In one embodiment, the process comprises measuring the alcohol contentof an aqueous solution of phenobarbital or salts thereof. In oneembodiment, if the alcohol content of the aqueous solution is below 5000ppm then the process further comprises a step of adding an alcohol in aquantity that is sufficient to achieve the alcohol content of at leastabout 5000 ppm.

In one embodiment, the process comprises measuring the alcohol contentof the lyophilized pharmaceutical composition of phenobarbital or saltsthereof. In one embodiment, the process may comprises an additional stepof lyophilization to achieve the alcohol content not more than about66000 ppm or not more than about 70000 ppm (whichever is desired). Inone embodiment, if the alcohol content is above about 66000 ppm or aboveabout 70000 ppm, the process further comprises repeating thelyophilization step till the alcohol content of the lyophilizedpharmaceutical composition is not more than about 66000 ppm or not morethan about 70000 ppm (whichever is desired). It is understood that evena single additional cycle of lyophilization would be sufficient or ithas to be repeated n number of times to obtain the desired alcohollevel.

In one embodiment, the process comprises addition of a pH modifier tothe aqueous solution of phenobarbital or salts thereof to achieve a pHin a range of 8-12, preferably in a range of 9-11, more preferably in arange of 9-10.5.

In one embodiment, the pH modifier is selected from HCl and/or NaOH. Inone embodiment, the pH modifier is aqueous HCl solution.

In one embodiment, the lyophilized pharmaceutical composition isreconstituted with water for injection, an aqueous saline or an aqueousdextrose solution. In one embodiment, the lyophilized pharmaceuticalcomposition is reconstituted with 0.9% aqueous saline.

In one embodiment, the pharmaceutical composition has an alcohol contentin the range from about 5000 ppm to about 66000 ppm or alternativelyfrom about 5000 ppm to about 70000 ppm. In one embodiment, the alcoholcontent is at least about 5000 ppm, about 10000 ppm, about 15000 ppm,about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm,about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm,about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm.In another embodiment, the alcohol content is in the range from about12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm orabout 12000 ppm to about 15000 ppm. In another embodiment, the alcoholcontent is in the range from about 15000 ppm to about 70000 ppm, about15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm orabout 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the pharmaceutical composition is an aqueous solutionfor injection of phenobarbital or salts thereof.

In one embodiment, the pharmaceutical composition comprise phenobarbitalor salts thereof in a concentration of 10-200 mg/ml. In one embodiment,phenobarbital or salts thereof is present in a concentration of 10mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml,150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

In one embodiment, the pharmaceutical composition is stable up to 12hours of storage at 20-25° C.

In one embodiment, the amount of total impurities present in thepharmaceutical composition following 12 hours of storage at 20-25° C.does not exceed 0.5%. In one embodiment, the amount of total impuritiespresent in the pharmaceutical composition following 12 hours of storageat 20-25° C. does not exceed 0.2%.

In one embodiment, the pharmaceutical composition is stable up to 36hours of storage at 2-8° C.

In one embodiment, the amount of total impurities present in thepharmaceutical composition following 36 hours of storage at 2-8° C. doesnot exceed 0.5%. In one embodiment, the amount of total impuritiespresent in the pharmaceutical composition following 36 hours of storageat 2-8° C. does not exceed 0.2%.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the osmolality of the pharmaceutical composition isbelow 500 mOsm/kg. In one embodiment, the osmolality of thepharmaceutical composition is about 300-400 mOsm/kg.

In one embodiment, the pharmaceutical composition is free of benzylalcohol.

In one embodiment, the pharmaceutical composition is also free ofpropylene glycol.

In a preferred embodiment, the pharmaceutical composition is free ofbenzyl alcohol and propylene glycol.

In order to achieve a desired stability, the pharmaceutical compositionshould have an alcohol content in the range from about 5000 ppm to 66000ppm or alternatively from about 5000 ppm to about 70000 ppm, and thusthe process may include the steps as discussed above for measuring thealcohol content, adding alcohol or removing additional alcohol byrepeating the lyophilization step and ensuring that the alcohol contentis achieved as described above.

In the ninth aspect, the present disclosure relates to a lyophilizedpharmaceutical composition comprising phenobarbital or salts thereof andan alcohol.

In one embodiment, the alcohol is present in an amount sufficient toinhibit phenobarbital degradation, such that the amount of totalimpurities present in the lyophilized pharmaceutical compositionfollowing 36 months of storage at 20-25° C. does not exceed 0.5%. In oneembodiment, the amount of total impurities present in the lyophilizedpharmaceutical composition following 36 months of storage at 20-25° C.does not exceed 0.2%.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the amount of alcohol sufficient to inhibitphenobarbital degradation is in the range from about 5000 ppm to about66000 ppm or alternatively from about 5000 ppm to about 70000 ppm. Inone embodiment, the alcohol content is at least about 5000 ppm, about10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about66000 ppm, or about 70000 ppm. In another embodiment, the alcoholcontent is in the range from about 12000 to about 70000 ppm, about 12000ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about 12000ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about 12000ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about 12000ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about 12000ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about 12000ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. In anotherembodiment, the alcohol content is in the range from about 15000 ppm toabout 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm toabout 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppm toabout 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppm toabout 55000 ppm or about 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the lyophilized pharmaceutical composition is stableup to 36 months of storage at 20-25° C.

In one embodiment, the lyophilized pharmaceutical composition is free ofbenzyl alcohol.

In one embodiment, the lyophilized pharmaceutical composition is alsofree of propylene glycol.

In a preferred embodiment, the lyophilized pharmaceutical composition isfree of benzyl alcohol and propylene glycol.

In one embodiment, the present disclosure relates to a lyophilizedpharmaceutical composition comprising phenobarbital sodium and ethanol,wherein ethanol is present in an amount sufficient to inhibitdegradation of phenobarbital sodium, such that the amount of totalimpurities present in the lyophilized pharmaceutical compositionfollowing 36 months of storage at 20-25° C. does not exceed 0.2%;

wherein the amount of ethanol sufficient to inhibit degradation ofphenobarbital sodium is in the range from about 12000 ppm to about 25000ppm;

and wherein the pharmaceutical composition is free of benzyl alcohol andpropylene glycol.

In the tenth aspect, the present disclosure relates to an aqueoussolution for injection comprising phenobarbital or salts thereof and analcohol.

In one embodiment, the aqueous solution for injection is reconstitutedfrom the lyophilized pharmaceutical composition of phenobarbital orsalts thereof.

In one embodiment, the lyophilized pharmaceutical composition isreconstituted with water for injection, an aqueous saline or an aqueousdextrose solution.

In one embodiment, the alcohol is present in an amount sufficient toinhibit phenobarbital degradation, such that the amount of totalimpurities present in the aqueous solution following 12 hours of storageat 20-25° C. does not exceed 0.5%. In one embodiment, the amount oftotal impurities present in the aqueous solution following 12 hours ofstorage at 20-25° C. does not exceed 0.2%.

In one embodiment, the alcohol is present in an amount sufficient toinhibit phenobarbital degradation, such that the amount of totalimpurities present in the aqueous solution following 36 hours of storageat 2-8° C. does not exceed 0.5%. In one embodiment, the amount of totalimpurities present in the aqueous solution following 36 hours of storageat 2-8° C. does not exceed 0.2%.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the amount of alcohol sufficient to inhibitphenobarbital degradation is in the range from about 5000 ppm to about66000 ppm or alternatively from about 5000 ppm to about 70000 ppm. Inone embodiment, the alcohol content is at least about 5000 ppm, about10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm, about50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm, about66000 ppm, or about 70000 ppm. In another embodiment, the alcoholcontent is in the range from about 12000 ppm to about 70000 ppm, about12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. Inanother embodiment, the alcohol content is in the range from about 15000ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppmto about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppmto about 55000 ppm or about 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the aqueous solution comprise phenobarbital or saltsthereof in a concentration of 10-200 mg/ml. In one embodiment,phenobarbital or salts thereof is present in a concentration of 10mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml,150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

In one embodiment, the aqueous solution is stable up to 12 hours ofstorage at 20-25° C.

In one embodiment, the aqueous solution is stable up to 36 hours ofstorage at 2-8° C.

In one embodiment, the osmolality of the aqueous solution is below 500mOsm/kg. In one embodiment, the osmolality of the aqueous solution isabout 300-400 mOsm/kg.

In one embodiment, the aqueous solution is free of benzyl alcohol.

In one embodiment, the aqueous solution is also free of propyleneglycol.

In a preferred embodiment, the aqueous solution is free of benzylalcohol and propylene glycol.

In one embodiment, the present disclosure relates to an aqueous solutionfor injection comprising phenobarbital sodium and ethanol, whereinethanol is present in an amount sufficient to inhibit degradation ofphenobarbital sodium, such that the amount of total impurities presentin the aqueous solution following 12 hours of storage at 20-25° C. orfollowing 36 hours of storage at 2-8° C. does not exceed 0.2%;

wherein the amount of ethanol sufficient to inhibit degradation ofphenobarbital sodium is in the range from about 12000 ppm to about 25000ppm;

wherein phenobarbital sodium is present in a concentration from 10-200mg/ml;

wherein the aqueous solution is reconstituted from the lyophilizedpharmaceutical composition of phenobarbital sodium;

and wherein the aqueous solution is free of benzyl alcohol and propyleneglycol.

In the eleventh aspect, the present disclosure relates to a process forthe preparation of the pharmaceutical composition of phenobarbital orsalts thereof, wherein the process comprises dissolving phenobarbital orsalt thereof in water to obtain an aqueous solution having aconcentration 10-200 mg/ml and lyophilizing the aqueous solution toobtain lyophilized pharmaceutical composition, wherein phenobarbital orsalts thereof has an alcohol content in the range from about 5000 ppm toabout 66000 ppm or alternatively from about 5000 ppm to about 70000 ppm.

In one embodiment, the process comprises phenobarbital or salts thereofhaving an alcohol content in the range from about 5000 ppm to about66000 ppm or alternatively from about 5000 ppm to about 70000 ppm. Inone embodiment, the active pharmaceutical ingredient of phenobarbital orsalts thereof for the purpose of this aspect is having an alcoholcontent in the range from about 5000 ppm to about 66000 ppm oralternatively from about 5000 ppm to about 70000 ppm.

In one embodiment, the process further comprises reconstitution of thelyophilized pharmaceutical composition. In one embodiment, thelyophilized pharmaceutical composition is reconstituted with water forinjection, an aqueous saline or an aqueous dextrose solution. In oneembodiment, the lyophilized pharmaceutical composition is reconstitutedwith 0.9% aqueous saline.

In one embodiment, phenobarbital or salts thereof has an alcohol contentof at least about 5000 ppm, about 10000 ppm, about 15000 ppm, about20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm, about40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm, about60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm. Inanother embodiment, the alcohol content is in the range from about 12000ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about 12000ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about 12000ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about 12000ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about 12000ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about 12000ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm or about12000 ppm to about 15000 ppm. In another embodiment, the alcohol contentis in the range from about 15000 ppm to about 70000 ppm, about 15000 ppmto about 66000 ppm, about 25000 ppm to about 66000 ppm, about 35000 toabout 66000 ppm, about 45000 ppm to about 66000 ppm, about 55000 ppm toabout 66000 ppm, about 35000 ppm to about 55000 ppm or about 30000 ppmto about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the pharmaceutical composition is free of benzylalcohol.

In one embodiment, the pharmaceutical composition is also free ofpropylene glycol.

In a preferred embodiment, the pharmaceutical composition is free ofbenzyl alcohol and propylene glycol.

In one embodiment, the pharmaceutical composition is lyophilizedpharmaceutical composition of phenobarbital or salts thereof.

In one embodiment, the lyophilized pharmaceutical composition is stableup to 36 months of storage at 20-25° C.

In one embodiment, the amount of total impurities present in thelyophilized pharmaceutical composition following 36 months of storage at20-25° C. does not exceed 0.5%. In one embodiment, the amount of totalimpurities present in the lyophilized pharmaceutical compositionfollowing 36 months of storage at 20-25° C. does not exceed 0.2%.

In one embodiment, the pharmaceutical composition is an aqueous solutionfor injection of phenobarbital or salts thereof.

In one embodiment, the aqueous solution comprise phenobarbital or saltsthereof in a concentration of 10-200 mg/ml. In one embodiment,phenobarbital or salts thereof is present in a concentration of 10mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml,150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

In one embodiment, the aqueous solution is stable up to 12 hours ofstorage at 20-25° C.

In one embodiment, the amount of total impurities present in the aqueoussolution following 12 hours of storage at 20-25° C. does not exceed0.5%. In one embodiment, the amount of total impurities present in theaqueous solution following 12 hours of storage at 20-25° C. does notexceed 0.2%.

In one embodiment, the aqueous solution is stable up to 36 hours ofstorage at 2-8° C.

In one embodiment, the amount of total impurities present in the aqueoussolution following 36 hours of storage at 2-8° C. does not exceed 0.5%.In one embodiment, the amount of total impurities present in the aqueoussolution following 36 hours of storage at 2-8° C. does not exceed 0.2%.

In one embodiment, the osmolality of the aqueous solution is below 500mOsm/kg. In one embodiment, the osmolality of the aqueous solution isabout 300-400 mOsm/kg.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In another aspect, the present disclosure relates to a lyophilizedpharmaceutical composition of phenobarbital or salts thereof, whereinthe lyophilized pharmaceutical composition has: (i) an amount of alcoholpresent following 36 months of storage at 20-25° C. in the range fromabout 5000 ppm to about 66000 ppm or alternatively from about 5000 ppmto about 70000 ppm; or (ii) an amount of total impurities presentfollowing 36 months of storage at 20-25° C. does not exceed 0.2%.

In one embodiment, the lyophilized pharmaceutical composition has anamount of alcohol present following 36 months of storage at 20-25° C. inthe range from about 5000 ppm to about 66000 ppm or alternatively fromabout 5000 ppm to about 70000 ppm. In one embodiment, the alcoholcontent is at least about 5000 ppm, about 10000 ppm, about 15000 ppm,about 20000 ppm, about 25000 ppm, about 30000 ppm, about 35000 ppm,about 40000 ppm, about 45000 ppm, about 50000 ppm, about 55000 ppm,about 60000 ppm, about 65000 ppm, about 66000 ppm, or about 70000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm orabout 12000 ppm to about 15000 ppm. In another embodiment, the alcoholcontent is in the range from about 15000 ppm to about 70000 ppm, about15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm orabout 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the lyophilized pharmaceutical composition is stableup to 36 months of storage at 20-25° C.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the lyophilized pharmaceutical composition is free ofbenzyl alcohol.

In one embodiment, the lyophilized pharmaceutical composition is alsofree of propylene glycol.

In a preferred embodiment, the lyophilized pharmaceutical composition isfree of benzyl alcohol and propylene glycol.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition of phenobarbital or salts thereof that has beenreconstituted from a lyophilized pharmaceutical composition ofphenobarbital or salts thereof, wherein the pharmaceutical compositionhas: (i) an amount of alcohol present following 12 hours of storage at20-25° C. or 36 hours of storage at 2-8° C. in the range from about 5000ppm to about 66000 ppm or alternatively from about 5000 ppm to about70000 ppm; or (ii) an amount of total impurities present following 12hours of storage at 20-25° C. or 36 hours of storage at 2-8° C. does notexceed 0.2%.

In one embodiment, the pharmaceutical composition has an amount ofalcohol present following 12 hours of storage at 20-25° C. or 36 hoursof storage at 2-8° C. in the range from about 5000 ppm to about 66000ppm or alternatively from about 5000 ppm to about 70000 ppm. In oneembodiment, the alcohol content is at least about 5000 ppm, about 10000ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm, about 30000 ppm,about 35000 ppm, about 40000 ppm, about 45000 ppm, about 50000 ppm,about 55000 ppm, about 60000 ppm, about 65000 ppm, about 66000 ppm, orabout 70000 ppm. In another embodiment, the alcohol content is in therange from about 12000 ppm to about 70000 ppm, about 12000 ppm to about66000 ppm, about 12000 ppm to about 65000 ppm, about 12000 ppm to about60000 ppm, about 12000 ppm to about 55000 ppm, about 12000 ppm to about50000 ppm, about 12000 ppm to about 45000 ppm, about 12000 ppm to about40000 ppm, about 12000 ppm to about 35000 ppm, about 12000 ppm to about30000 ppm, about 12000 ppm to about 25000 ppm, about 12000 ppm to about20000 ppm or about 12000 ppm to about 15000 ppm. In another embodiment,the alcohol content is in the range from about 15000 ppm to about 70000ppm, about 15000 ppm to about 66000 ppm, about 25000 ppm to about 66000ppm, about 35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm,about 55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppmor about 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In one embodiment, the lyophilized pharmaceutical composition isreconstituted with water for injection, an aqueous saline or an aqueousdextrose solution. In one embodiment, the lyophilized pharmaceuticalcomposition is reconstituted with 0.9% aqueous saline.

In one embodiment, the pharmaceutical composition is an aqueous solutionfor injection of phenobarbital or salts thereof.

In one embodiment, the pharmaceutical composition comprise phenobarbitalor salts thereof in a concentration of 10-200 mg/ml. In one embodiment,phenobarbital or salts thereof is present in a concentration of 10mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50 mg/ml, 60 mg/ml, 70 mg/ml, 80mg/ml, 90 mg/ml, 100 mg/ml, 110 mg/ml, 120 mg/ml, 130 mg/ml, 140 mg/ml,150 mg/ml, 160 mg/ml, 170 mg/ml, 180 mg/ml, 190 mg/ml and 200 mg/ml.

In one embodiment, the pharmaceutical composition is stable up to 12hours of storage at 20-25° C.

In one embodiment, the pharmaceutical composition is stable up to 36hours of storage at 2-8° C.

In one embodiment, the total impurities are selected from2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.

In one embodiment, the osmolality of said pharmaceutical composition isbelow 500 mOsm/kg. In one embodiment, the osmolality of said aqueoussolution is about 300-400 mOsm/kg.

In one embodiment, the pharmaceutical composition is free of benzylalcohol.

In one embodiment, the pharmaceutical composition is also free ofpropylene glycol.

In a preferred embodiment, the pharmaceutical composition is free ofbenzyl alcohol and propylene glycol.

In another aspect, the present disclosure relates to a lyophilizedpharmaceutical composition of phenobarbital sodium, wherein thecomposition has an ethanol content in the range from about 12000 ppm toabout 25000 ppm; wherein the composition is stable up to 36 months ofstorage at 20-25° C. such that the amount of total impurities presentfollowing 36 months of storage at 20-25° C. does not exceed 0.2%; andwherein the composition is free of benzyl alcohol and propylene glycol.

In another aspect, the present disclosure relates to an aqueous solutionfor injection of phenobarbital sodium, wherein the aqueous solution hasan ethanol content in the range from about 12000 ppm to about 25000 ppm;wherein the aqueous solution is stable up to 12 hours of storage at20-25° C. or 36 hours of storage at 2-8° C. such that the amount oftotal impurities present following 12 hours of storage at 20-25° C. orfollowing 36 hours of storage at 2-8° C. does not exceed 0.2%; whereinthe aqueous solution is reconstituted from the lyophilizedpharmaceutical composition of phenobarbital sodium; and wherein theaqueous solution is free of benzyl alcohol and propylene glycol.

In another aspect, the present disclosure relates to a method ofpreventing degradation of phenobarbital or salts thereof, wherein themethod comprises dissolving phenobarbital or salts thereof in water toobtain an aqueous solution having a concentration 10-200 mg/ml; andlyophilizing the aqueous solution to obtain lyophilized pharmaceuticalcomposition of phenobarbital or salts thereof, wherein the methodcomprises presence of alcohol, in an amount sufficient to inhibit thedegradation of phenobarbital or salts thereof.

In one embodiment, the present disclosure relates to reconstituting thelyophilized pharmaceutical composition to obtain the aqueous solutionfor injection of phenobarbital or salts thereof.

In one embodiment, wherein the amount of alcohol sufficient to inhibitdegradation of phenobarbital or salts thereof is in the range from about5000 ppm to about 66000 ppm or alternatively from about 5000 ppm toabout 70000 ppm. In one embodiment, the amount of alcohol is at leastabout 5000 ppm, about 10000 ppm, about 15000 ppm, about 20000 ppm, about25000 ppm, about 30000 ppm, about 35000 ppm, about 40000 ppm, about45000 ppm, about 50000 ppm, about 55000 ppm, about 60000 ppm, about65000 ppm, about 66000 ppm, or about 70000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 70000 ppm, about 12000 ppm to about 66000 ppm, about12000 ppm to about 65000 ppm, about 12000 ppm to about 60000 ppm, about12000 ppm to about 55000 ppm, about 12000 ppm to about 50000 ppm, about12000 ppm to about 45000 ppm, about 12000 ppm to about 40000 ppm, about12000 ppm to about 35000 ppm, about 12000 ppm to about 30000 ppm, about12000 ppm to about 25000 ppm, about 12000 ppm to about 20000 ppm orabout 12000 ppm to about 15000 ppm. In another embodiment, the alcoholcontent is in the range from about 15000 ppm to about 70000 ppm, about15000 ppm to about 66000 ppm, about 25000 ppm to about 66000 ppm, about35000 to about 66000 ppm, about 45000 ppm to about 66000 ppm, about55000 ppm to about 66000 ppm, about 35000 ppm to about 55000 ppm orabout 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

In yet another aspect, the present invention relates to phenobarbital orsalts thereof having an alcohol in an amount sufficient to inhibitdegradation of phenobarbital sodium.

In one embodiment, the amount of alcohol sufficient to inhibitdegradation of phenobarbital or salts thereof is such that when saidphenobarbital or salts thereof having an alcohol is stored for 36 monthsat 20-25° C., the amount of total impurities does not exceed 0.5%,preferably does not exceed 0.2%.

In an alternate embodiment, the amount of alcohol sufficient to inhibitdegradation of phenobarbital or salts thereof is such that when saidphenobarbital or salts thereof is dissolved in an aqueous media and isstored for 12 hours at 20-25° C. or 36 hours at 2-8° C., the amount oftotal impurities does not exceed 0.5%, preferably does not exceed 0.2%.In one embodiment, the amount of alcohol sufficient to inhibitdegradation of phenobarbital or salts thereof is from about 5000 ppm toabout 70000 ppm.

In one embodiment, the phenobarbital or salts thereof having an alcoholcontent in a range from about 5000 ppm to about 70000 ppm, is stable upto 36 months of storage at 20-25° C. such that the amount of totalimpurities present following 36 months of storage at 20-25° C. does notexceed 0.5%, preferably does not exceed 0.2%.

In another embodiment, the phenobarbital or salts thereof having analcohol content in a range from about 5000 ppm to about 70000 ppm, whendissolved in an aqueous media, the resulting aqueous solution ofphenobarbital or salts thereof remains stable up to 12 hours of storageat 20-25° C. or 36 hours of storage at 2-8° C. such that the amount oftotal impurities present following 12 hours of storage at 20-25° C. orfollowing 36 hours of storage at 2-8° C. does not exceed 0.5%,preferably does not exceed 0.2%.

In one embodiment, the amount of alcohol is at least about 5000 ppm,about 10000 ppm, about 15000 ppm, about 20000 ppm, about 25000 ppm,about 30000 ppm, about 35000 ppm, about 40000 ppm, about 45000 ppm,about 50000 ppm, about 55000 ppm, about 60000 ppm, about 65000 ppm,about 66000 ppm, or about 70000 ppm. In another embodiment, the alcoholcontent is in the range from about 12000 ppm to about 70000 ppm, about12000 ppm to about 66000 ppm, about 12000 ppm to about 65000 ppm, about12000 ppm to about 60000 ppm, about 12000 ppm to about 55000 ppm, about12000 ppm to about 50000 ppm, about 12000 ppm to about 45000 ppm, about12000 ppm to about 40000 ppm, about 12000 ppm to about 35000 ppm, about12000 ppm to about 30000 ppm, about 12000 ppm to about 25000 ppm, about12000 ppm to about 20000 ppm or about 12000 ppm to about 15000 ppm. Inanother embodiment, the alcohol content is in the range from about 15000ppm to about 70000 ppm, about 15000 ppm to about 66000 ppm, about 25000ppm to about 66000 ppm, about 35000 to about 66000 ppm, about 45000 ppmto about 66000 ppm, about 55000 ppm to about 66000 ppm, about 35000 ppmto about 55000 ppm or about 30000 ppm to about 50000 ppm.

In another embodiment, the alcohol content is in the range from about12000 ppm to about 25000 ppm. In one embodiment, the alcohol content isin the range from about 35000 to about 66000 ppm.

In one embodiment, the alcohol is a C₁-C₃ alcohol.

In one embodiment, the alcohol is ethanol.

In one embodiment, phenobarbital or salts thereof is phenobarbital baseor phenobarbital sodium, preferably phenobarbital sodium.

Through lyophilization, the present inventors have found that thealcohol content of phenobarbital sodium may be reduced to less than50000 ppm. The present inventors have found that in some embodiments,the alcohol content may be reduced to a level of about 5000 ppm. Thepresent inventors have found that the low temperature vacuum dryingconditions afforded by lyophilization provide a safe and effectivemechanism for converting the tested material to a solid state.Lyophilization, also known as freeze drying, may consist of threeseparate, unique, and interdependent process; freezing, primary drying(sublimation) and secondary drying (desorption).

In certain preferred embodiments, the step of freezing the aqueoussolution may occur at a temperature range of −20 to −50° C. In certainpreferred embodiments, the step drying the aqueous solution may occur atprimary and/or secondary temperature ranges of −35 to 25° C. However, itshould be understood that these temperatures are exemplary only, andtemperatures may be chosen so as to optimize the lyophilized powder.Where secondary temperature ranges are used, the step of drying may besplit into two separate steps, each occurring at a different temperatureand a different time. In certain preferred embodiments, there may alsobe performed a step of annealing the aqueous solution, which may occurat a temperature range of −15 to −25°. In certain embodiments, a desiredlevel of residual water content after lyophilization may be less than 3%w/w.

As illustrated in the Examples below, the present inventors haveobserved that the use of certain level of alcohol and lyophilization inthe development of the pharmaceutical composition of phenobarbital orslats thereof provides for greatly improved stability in the resultingproduct.

EXAMPLES

HPLC Method:

-   -   HPLC instrument with UV detector or PDA detector;    -   Reagents/Solvents: Potassium dihydrogen phosphate,        Orthophosphoric acid, Acetonitrile, Methanol, Water, Water for        Injection;    -   Needle wash solutions—Water:Methanol (20:80 v/v) & Column wash        solution—Water Acetonitrile (50:50 v/v);    -   Preparation of diluted orthophosphoric acid: Dilute 1 ml of        concentrated orthophosphoric acid to 10 ml with water;    -   Preparation of Buffer: Weigh about 2.9 g (2.85 g to 2.95 g) of        potassium dihydrogen phosphate and dissolve in 1000 ml of        Milli-Q water, adjust pH to 3.5±0.05 with dilute orthophosphoric        acid.    -   Filter the solution through 0.45 PVDF Merck Durapore membrane or        equivalent filter.

Preparation of Mobile Phase Solutions: Mobile Phase A: Buffer toAcetonitrile (80:20) & Mobile Phase B: Buffer to Acetonitrile (50:50);Diluent: water:methanol (20:80)

Chromatographic Conditions:

-   -   Column Zorbax Eclipse XDB Phenyl, 150×4.6 mm, 5 m (Agilent)    -   Column temperature 40° C.    -   Sample Cooler 10° C.    -   Flow rate 1.2 ml/min    -   Injection Volume 10 μl    -   Wavelength 210 nm (UV/PDA)    -   Run Time 15 minutes

HPLC Gradient:

Time (minute) Mobile phase A % Mobile phase B % 0 80 20 4 80 20 7 20 8012 20 80 12.1 80 20 15 80 20

Example 1

In a clean and dry flask, 1000 mg of phenobarbital base and 1.67 ml of96% ethanol were combined and mixed for 1 minute. To this solution,1.722 ml of the 10% NaOH solution was added and was mixed for 15minutes. Water for injection sufficient to raise the volume to 25 ml wasthen added and the resulting solution was mixed for 2 minutes andfiltered through a 0.2 micron PES filter.

Example 2

The procedures of Example 1 were followed, with the exception thatethanol was not added and the batch size was 600 ml.

The bulk solutions of both the examples were analyzed and the resultsare shown in Table 1 below:

TABLE 1 Example 1 Example 2 With additional Without additional EthanolEthanol Phenobarbital base Less than 5000 ppm ethanol Initial analysis0M 0M Total Impurity (%) 0.06 0.314

Table 1 illustrates that the impurity profile in the composition withadditional ethanol (example 1) is better than the composition withoutethanol (example 2). It is to be noted that the phenobarbital base APIas used in these examples had an ethanol content of less than 5000 ppm.Thus, the composition of example 1, comprises an ethanol content above5000 ppm. Whereas, the composition of example 2 comprises no additionalethanol and thus the amount of ethanol in the composition of example 2is equal to the amount present in phenobarbital base API (less than 5000ppm) or less.

Example 3

In a clean and dry vessel, 3.64 g phenobarbital base and water forinjection were mixed by stirring until the phenobarbital base wasdissolved. 6.3 ml of an aqueous 10% NaOH solution was then added whilestirring. Water for injection was then added to bring the volume up to100 ml and the resulting mixture was stirred for 2 minutes.

Example 4

The procedures of Example 3 were followed, with the exception thatfollowing the step of dissolving phenobarbital in water for injection,6.3 mL of 96% ethanol was added to the mixture. As with Example 3, 6.3mL of an aqueous 10% NaOH solution was then added while stirring. Waterfor injection was then added to bring the volume up to 100 ml and theresulting mixture was stirred for 2 minutes.

The results for Examples 3 and 4 are shown in Table 2 below:

TABLE 2 Example 3 Example 4 Without additional ethanol With additionalethanol Phenobarbital Less than 5000 ppm ethanol base Total Impurities(%) Stage of Analysis 2-8° C. 20-25° C. 2-8° C. 20-25° C. 0 hr 0.3860.386 0.344 0.344 8 hr 0.969 2.526 0.735 1.93 24 hr  5.065 7.423 3.9825.586

Table 2 illustrates that adding ethanol to the phenobarbital compositionin the amounts tested above provided for fewer impurities than thecomposition that did not have additional ethanol. Ethanol content of5000 ppm is not sufficient to prevent formation of impurities. Thecomposition wherein additional ethanol was added, afforded a productwith improved stability. Degradation of such composition when subjectedto stability testing was found to be significantly lower than thecomposition wherein there was no additional ethanol addition.

Example 5

In a clean and dry vessel, 4 g of phenobarbital sodium was dissolved viastirring in water for injection. 6.3 ml of 96% ethanol was added to thesolution while stirring, and water for injection was then added in anamount sufficient to raise the volume to 100 ml. The resulting solutionwas stirred for 2 minutes.

Example 6

The procedures of Example 5 were reproduced, with the exception that thepH of the final solution was adjusted to 9.0 by using 0.1N HCl.

Example 7

The procedures of Example 5 were reproduced, with the exception that theethanol was not added.

Example 8

The procedures of Example 6 were reproduced, with the exception that theethanol was not added It is to be noted that the phenobarbital sodiumAPI as used in these examples had an ethanol content of about 66000 ppm.

The results of Examples 5-8 are shown in Table 3 below:

TABLE 3 Composition with Phenobarbital Sodium Example 5 Example 6Example 7 Example 8 Phenobarbital About 66000 ppm ethanol Na 40 mg 40 mg40 mg 40 mg Ethanol 96% 0.063 ml   0.063 ml   — — pH of Solution 9.789.02 9.61 9.04 Total Impurities (%) (2-8° C.) 0 h 0.004 0.005 0.0070.005 1 h 0.012 0.011 0.016 0.011 2 h 0.025 0.014 0.028 0.017 4 h 0.0260.017 0.031 0.018 8 h 0.028 0.016 0.032 0.02 24 h  0.04 0.015 0.0520.022

Table 3 shows that when the amount of ethanol present in phenobarbitalsodium composition was above 5000 ppm then the formation of totalimpurities was minimized.

Example 9

In a clean and dry vessel, 60 g of phenobarbital sodium was dissolvedvia stirring in 1000 ml water for injection and further added 94.5 mL of96% ethanol. The clarity of the solution was reviewed to ensure that itwas clear, and then water for injection sufficient to raise the volumeto 1500 ml was added and the solution was stirred followed by filteredthrough a 0.2 micron PES filter and lyophilization. The lyophilizedphenobarbital sodium was kept on stability at 2-8° C. for 36 months. Thelyophilized phenobarbital sodium was analyzed for ethanol content atregular intervals.

Example 10

The procedures of Example 9 were reproduced, with the exception that thepH was adjusted to 9 by the use of 5% HCl and then lyophilized. Thelyophilized phenobarbital sodium was kept on stability at 2-8° C. for 36months. The lyophilized phenobarbital sodium was analyzed for ethanolcontent at regular intervals.

It is to be noted that the phenobarbital sodium API as used in theseexamples had an ethanol content of about 66000 ppm.

The results of Examples 9 and 10 are shown in Table 4 below:

TABLE 4 Example 9 Example 10 Initial 38474.7 53078.7  1M 52188.3 66539.3 3M 46489.6 54457  6M 34028.5 49584.1 12M 37039.5 45440 18M 42227.553834.1 24M 38035 46805 36M 45139 52043

Table 4 shows that when additional ethanol is added in the compositionsfollowed by lyophilizing the solution, the amount of ethanol present inthe tested compositions were within the range of from about 34000 ppm toabout 66000 ppm.

Example 11

In a clean and dry vessel, 64 g of phenobarbital sodium was dissolvedvia stirring in 1200 ml water for injection and the clarity of thesolution was observed to ensure that it was clear. Water for injectionwas then added to the solution in an amount sufficient to raise thevolume to 1600 ml and the solution was stirred, filtered through a 0.2micron PES filter and lyophilized. The lyophilized phenobarbital sodiumwas kept on stability at 20-25° C. for 36 months. The lyophilizedphenobarbital sodium was analyzed for ethanol content at regularintervals.

Example 12

The procedures of Example 11 were reproduced, with the exception thatthe batch size was 1800 ml. The lyophilized phenobarbital sodium waskept on stability at 20-25° C. for 36 months. The lyophilizedphenobarbital sodium was analyzed for ethanol content at regularintervals.

It is to be noted that the phenobarbital sodium API as used in theseexamples had an ethanol content of about 66000 ppm.

The results of Examples 11 and 12 were are shown in Table 5 below:

TABLE 5 West-ward's Example 11 Example 12 Composition* Phenobarbitalsodium About 66000 ppm ethanol Ethanol — 0.1 ml/ml Stage of Analysis 24M36M 24M 36M analysis after 2.1 year Solvents (Ethanol in ppm) 1880216680 17030 13826 66436.1 Unknown Impurities 0.057 0.029 0.019 0.0332.113 (Highest Unspecified) (%) Total Impurities (%) 0.138 0.047 0.0390.067 2.187 Osmolality (mOsm/kg) 370 371 361 357 1341 *West-ward’scomposition is Phenobarbital sodium in ethanol, benzyl alcohol andpropylene glycol

Table 5 illustrates that despite the use of a higher level of ethanol ina West-ward's product of phenobarbital sodium at 65 mg/ml, theimpurities formation therein is higher than the pharmaceuticalcomposition of preferred embodiments of the present disclosure.Accordingly, the optimum amount of ethanol and lyophilization may beachieved so as to provide for the greatest control of impurities in thecomposition.

During storage, the amount of ethanol present in the composition maydecrease to about 12000 ppm, and thus composition containing ethanol ina range of 12000 to 66000 ppm provide for controlled and lowered levelsof impurities. The products of example 11 and 12 were subjected tostability testing. The results of the stability tests are shown in Table6 below:

TABLE 6 Example 11 Example 12 Initial 24333 15510.7  1M 18321 15639.7 3M 22172.2 15540  6M 23154.3 15034 12M 22891 15018 18M 18496 12307 24M18802 17030 36M 16680 13826

Table 6 shows that the amount of ethanol present in the testedcompositions was within the range of about 12000 ppm to about 25000 ppm.

Examples 13 & 14

In a clean and dry vessel, ˜50 L of water for injection was added andmaintained at 2-8° C. Nitrogen purging was performed for 30 min. ˜2.0 kgof phenobarbital sodium was dissolved via stirring for 5-10 min. in tothe water for injection and the clarity of the solution was observed toensure that it was clear. Solution was filtered through a 0.2 micron PESfilter and lyophilized. Ethanol content in the lyophilized phenobarbitalsodium was measured to be about 13114 ppm. The lyophilized phenobarbitalsodium was kept on stability at 20-25° C. for 36 months. Manufacturedbatch was also evaluated for reconstitution (in-use) stability. Drugproduct was reconstituted in 0.9% sodium chloride injection and storedat 20-25° C. and 2-8° C. for its stability evaluation. Reconstitutedsolution was analyzed at predefined time intervals.

It is to be noted that the phenobarbital sodium API as used in theseexamples had an ethanol content of about 70000 ppm.

The results of examples 13 were as shown in Table 7 below:

TABLE 7 Storage 20-25° C. 2-8° C. Stage of analysis 0 h 4 h 8 h 12 h 0 h12 h 24 h 36 h Unknown BQL BQL 0.053 0.101 BQL 0.072 BQL BQL impurity(highest unspecified) (%) Total impurity BQL BQL 0.053 0.101 BQL 0.072BQL BQL (%) Osmolality 365 371 366 366 371 366 364 368 mOsm/kg BQL:Below Quantitation Limit (0.05%)

The results of examples 14 were as shown in Table 8 below:

TABLE 8 Storage 20-25° C. 2-8° C. Stage of analysis 0 h 4 h 8 h 12 h 0 h12 h 24 h 36 h Unknown BQL BQL BQL 0.088 BQL 0.063 BQL BQL impurity(highest unspecified) (%) Total impurity BQL BQL BQL 0.088 BQL 0.063 BQLBQL (%) Osmolality 367 369 369 365 367 367 369 365 mOsm/kg BQL: BelowQuantitation Limit (0.05%)

Examples 15 and 16

Two 10% NaOH solutions were prepared in 50 ml flasks by mixing 5 g NaOHwith water for injection sufficient to make 30 ml of solution. Theresulting solution was mixed and shaken well.

To prepare a bulk solution containing alcohol (example 15), 36.4 mgphenobarbital was placed in a clean and dry vessel. 0.045 ml of a 96%ethanol was added and the resultant was shaken and subject to a vortexfor 1 minute. To this solution 0.063 ml of a 10% NaOH solution preparedpreviously was added and the resultant was subject to a vortex for 15minutes. Water for injection sufficient to make 1 ml solution was thenadded and the resultant was subject to a vortex for 10 minutes. Theresulting solution was transferred to a measuring cylinder and the pHwas checked and adjusted by 0.1N HCl to be 9.78. Water for injection wasadded to obtain 1 ml of solution and the solution was stirred for 2minutes. The resulting solution was filtered through a 0.2 micron PESfilter, and the filtrate was collected and kept at room temperature(20-25° C.) or 2-8° C. until analysis.

To prepare a bulk solution free from alcohol (example 16), 36.4 mgphenobarbital was placed in a clean and dry vessel. 0.045 ml of a 10%NaOH solution prepared previously was added and the resultant wassubject to a vortex for 15 minutes. Water for injection sufficient tomake 1 ml solution was then added and the resultant was subject to avortex for 10 minutes. The resulting solution was transferred to ameasuring cylinder and the pH was checked and adjusted by 0.1N HCl to be9.74. Water for injection was added to obtain 1 ml of solution and thesolution was stirred for 2 minutes. The resulting solution was filteredthrough a 0.2 micron PES filter, and the filtrate was collected and keptat room temperature (20-25° C.) or 2-8° C. until analysis.

The two bulk solutions were analyzed at set time periods and Table 9shows the results.

TABLE 9 Example Impurity 20-25° C. 2-8° C. 15 0 h 12 h 24 h 36 h 0 h 24h 36 h Unknown 0.042 0.371 0.708 1.002 0.042 0.151 0.219 impurity(highest unspecified) (%) Total 0.064 0.398 0.764 1.091 0.064 0.1730.236 Impurity (%) Example Unknown 0.065 0.634 1.207 1.724 0.065 0.2690.384 16 impurity (highest unspecified) (%) Total 0.078 0.674 1.2881.859 0.078 0.293 0.404 Impurity(%)

Even though certain specific embodiments are thoroughly described in thepresent application, it should be understood that the same conceptsdisclosed with respect to those specific embodiments are also applicableto other embodiments. Furthermore, individual elements of thecompositions and methods disclosed herein are described with referenceto particular embodiments only for the sake of convenience. It should beunderstood that individual elements of the compositions and methodsdisclosed herein are applicable to embodiments other than the specificembodiments in which they are described.

In addition, it should be understood that the scope of the presentdisclosure is not limited to the above-described embodiments, and thoseskilled in the art will appreciate that various modifications andalterations are possible without departing from the scope of the presentdisclosure. For example, the batch sizes may be altered by a personhaving ordinary skill in the art while staying within the presentdisclosure.

Features of the Invention

-   -   A1. A pharmaceutical composition of phenobarbital or salts        thereof that has been reconstituted from a lyophilized        pharmaceutical composition of phenobarbital or salts thereof,        wherein the amount of total impurities in the pharmaceutical        composition does not exceed 0.2% following 12 hours of storage        at 20-25° C. or 36 hours of storage at 2-8° C.    -   A2. The pharmaceutical composition of feature A1, wherein the        pharmaceutical composition has an alcohol content in the range        from about 5000 ppm to about 66000 ppm or alternatively from        about 5000 ppm to about 70000 ppm.    -   A3. The pharmaceutical composition of feature A1, wherein the        pharmaceutical composition has an alcohol content is in the        range from about 12000 ppm to about 66000 ppm.    -   A4. The pharmaceutical composition of feature A1, wherein the        pharmaceutical composition has an alcohol content is in the        range from about 12000 ppm to about 25000 ppm.    -   A5. The pharmaceutical composition of features A2-4, wherein        alcohol is a C₁-C₃ alcohol, such as ethanol.    -   A6. The pharmaceutical composition of feature A1, wherein        phenobarbital or salts thereof is phenobarbital sodium.    -   A7. The pharmaceutical composition of feature A1, wherein the        total impurities are selected from 2-phenyl-2-ethyl acetyl urea,        2-phenyl-2-ethyl-malonamide, α-phenylbutyrylguanidine,        2-phenylbutyric acid and 5-methyl-5-phenylbarbituric acid.    -   A8. The pharmaceutical composition of feature A1, wherein the        lyophilized pharmaceutical composition is reconstituted with        water for injection, an aqueous saline or an aqueous dextrose        solution.    -   A9. The pharmaceutical composition of feature A1, wherein the        pharmaceutical composition is an aqueous solution for injection        of phenobarbital or salts thereof.    -   A10. The pharmaceutical composition of feature A1, wherein        phenobarbital or salts thereof is present in a concentration of        10-200 mg/ml.    -   A11. The pharmaceutical composition of feature A1, wherein the        pharmaceutical composition is free of benzyl alcohol.    -   A12. The pharmaceutical composition of feature A1, wherein the        pharmaceutical composition is free of propylene glycol.    -   A13. The pharmaceutical composition of feature A1, wherein the        pharmaceutical composition has an osmolality below 500 mOsm/kg.    -   A14. A method for the treatment of neonatal seizure in newborn        infants of 2 weeks of age or younger in need thereof, comprising        administering the pharmaceutical composition of phenobarbital or        salts thereof that has been reconstituted from a lyophilized        pharmaceutical composition of phenobarbital or salts thereof,        wherein the amount of total impurities in the pharmaceutical        composition does not exceed 0.2% following 12 hours of storage        at 20-25° C. or 36 hours of storage at 2-8° C.    -   A15. The method of feature A14, wherein the pharmaceutical        composition is administered intravenously by infusion at a dose        of 20 mg/kg over a course of 15 minutes.    -   A16. The method of feature A14, wherein the method comprises        administering the pharmaceutical composition at an initial        loading dose of 20 mg/kg over a course of 15 minutes and        measuring the electrographic seizures; and if electrographic        seizures persist or recur after completion of the initial        loading dose, a second dose of 20 mg/kg is administered over        subsequent 15 minutes for a total loading dose of 40 mg/kg.    -   A17. The method of feature A14, wherein the method comprises        administering the pharmaceutical composition to neonates in whom        correctable abnormalities have been excluded or corrected.    -   A18. The method of feature A17, wherein the correctable        abnormalities are selected from hypoglycemia or hypocalcemia.    -   A19. The method of feature A14, wherein the pharmaceutical        composition has an alcohol content in the range from about 5000        ppm to about 66000 ppm or alternatively from about 5000 ppm to        about 70000 ppm.    -   A20. The method of feature A14, wherein the pharmaceutical        composition has an alcohol content is in the range from about        12000 ppm to about 66000 ppm.    -   A21. The method of feature A14, wherein the pharmaceutical        composition has an alcohol content is in the range from about        12000 ppm to about 25000 ppm.    -   A22. The method of features A19-21, wherein alcohol is a C₁-C₃        alcohol, such as ethanol.    -   A23. The method of feature A14, wherein phenobarbital or salts        thereof is phenobarbital sodium.    -   A24. The method of feature A14, wherein the total impurities are        selected from 2-phenyl-2-ethyl acetyl urea,        2-phenyl-2-ethyl-malonamide, α-phenylbutyrylguanidine,        2-phenylbutyric acid and 5-methyl-5-phenylbarbituric acid.    -   A25. The method of feature A14, wherein the lyophilized        pharmaceutical composition is reconstituted with water for        injection, an aqueous saline or an aqueous dextrose solution.    -   A26. The method of feature A14, wherein the pharmaceutical        composition is an aqueous solution for injection of        phenobarbital or salts thereof.    -   A27. The method of feature A14, wherein phenobarbital or salts        thereof is present in a concentration of 10-200 mg/ml.    -   A28. The method of feature A14, wherein the pharmaceutical        composition is free of benzyl alcohol.    -   A29. The method of feature A14, wherein the pharmaceutical        composition is free of propylene glycol.    -   A30. The method of feature A14, wherein the pharmaceutical        composition has an osmolality below 500 mOsm/kg.    -   A31. A pharmaceutical composition of phenobarbital or salts        thereof, wherein the pharmaceutical composition has an alcohol        content in the range from about 5000 ppm to about 66000 ppm or        alternatively from about 5000 ppm to about 70000 ppm.    -   A32. The pharmaceutical composition of feature A31, wherein the        composition has an alcohol content in the range from about 12000        ppm to about 66000 ppm.    -   A33. The pharmaceutical composition of feature A31, wherein the        composition has an alcohol content in the range from about 12000        ppm to about 25000 ppm.    -   A34. The pharmaceutical composition of features A31-33, wherein        alcohol is a C₁-C₃ alcohol, such as ethanol.    -   A35. The pharmaceutical composition of feature A31, wherein        phenobarbital or salts thereof is phenobarbital sodium.    -   A36. The pharmaceutical composition of feature A31, wherein the        pharmaceutical composition is a lyophilized pharmaceutical        composition of phenobarbital or salts thereof.    -   A37. The pharmaceutical composition of feature A36, wherein the        lyophilized pharmaceutical composition is stable up to 36 months        of storage at 20-25° C.    -   A38. The pharmaceutical composition of feature A37, wherein the        amount of total impurities present following 36 months of        storage at 20-25° C. does not exceed 0.5%.    -   A39. The pharmaceutical composition of feature A37, wherein the        amount of total impurities present following 36 months of        storage at 20-25° C. does not exceed 0.2%.    -   A40. The pharmaceutical composition of feature A31, wherein the        pharmaceutical composition is an aqueous solution for injection        of phenobarbital or salts thereof.    -   A41. The pharmaceutical composition of feature A40, wherein the        aqueous solution is reconstituted from the lyophilized        pharmaceutical composition of phenobarbital or salts thereof.    -   A42. The pharmaceutical composition of feature A41, wherein the        lyophilized pharmaceutical composition of phenobarbital or salts        thereof is reconstituted with water for injection, an aqueous        saline or an aqueous dextrose solution.    -   A43. The pharmaceutical composition of feature A40, wherein        phenobarbital or salts thereof is present in a concentration of        10-200 mg/ml.    -   A44. The pharmaceutical composition of feature A40, wherein the        aqueous solution is stable up to 12 hours of storage at 20-25°        C.    -   A45. The pharmaceutical composition of feature A44, wherein the        amount of total impurities present following 12 hours of storage        at 20-25° C. does not exceed 0.5%.    -   A46. The pharmaceutical composition of feature A44, wherein the        amount of total impurities present following 12 hours of storage        at 20-25° C. does not exceed 0.2%.    -   A47. The pharmaceutical composition of feature A40, wherein the        aqueous solution is stable up to 36 hours of storage at 2-8° C.    -   A48. The pharmaceutical composition of feature A47, wherein the        amount of total impurities present following 36 hours of storage        at 2-8° C. does not exceed 0.5%.    -   A49. The pharmaceutical composition of feature A47, wherein the        amount of total impurities present following 36 hours of storage        at 2-8° C. does not exceed 0.2%.    -   A50. The pharmaceutical composition of feature A40, wherein the        aqueous solution has an osmolality below 500 mOsm/kg.    -   A51. The pharmaceutical composition of features A38-39, A45-46        and A48-49, wherein the total impurities are selected from        2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,        α-phenylbutyrylguanidine, 2-phenylbutyric acid and        5-methyl-5-phenylbarbituric acid.    -   A52. The pharmaceutical composition of feature A31, wherein the        pharmaceutical composition is free of benzyl alcohol.    -   A53. The pharmaceutical composition of feature A31, wherein the        pharmaceutical composition is free of propylene glycol.    -   A54. A method for the treatment of neonatal seizure in newborn        infants of 2 weeks of age or younger in need thereof, comprising        administering the pharmaceutical composition of phenobarbital or        salts thereof, wherein the pharmaceutical composition has an        alcohol content in the range from about 5000 ppm to about 66000        ppm or alternatively from about 5000 ppm to about 70000 ppm.    -   A55. The method of feature A54, wherein the pharmaceutical        composition is administered intravenously by infusion at a dose        of 20 mg/kg over a course of 15 minutes.    -   A56. The method of feature A54, wherein the method comprises        administering the pharmaceutical composition at an initial        loading dose of 20 mg/kg over a course of 15 minutes and        measuring the electrographic seizures; and if the electrographic        seizures persist or recur after completion of the initial        loading dose, a second dose 20 mg/kg is administered over the        subsequent 15 minutes for a total loading dose of 40 mg/kg.    -   A57. The method of feature A54, wherein the method comprises        administering the pharmaceutical composition to neonates in whom        correctable abnormalities have been excluded or corrected.    -   A58. The method of feature A57, wherein the correctable        abnormalities are selected from hypoglycemia or hypocalcemia.    -   A59. The method of feature A54, wherein the pharmaceutical        composition has an alcohol content in the range from about 12000        ppm to about 66000 ppm.    -   A60. The method of feature A54, wherein the pharmaceutical        composition has an alcohol content in the range from about 12000        ppm to about 25000 ppm.    -   A61. The method of features A54, A59-60, wherein alcohol is a        C₁-C₃ alcohol, such as ethanol.    -   A62. The method of feature A54, wherein phenobarbital or salts        thereof is phenobarbital sodium.    -   A63. The method of feature A54, wherein the pharmaceutical        composition is a lyophilized pharmaceutical composition of        phenobarbital or salts thereof.    -   A64. The method of features A63, wherein the lyophilized        pharmaceutical composition is stable up to 36 months of storage        at 20-25° C.    -   A65. The method of features A64, wherein the amount of total        impurities present following 36 months of storage at 20-25° C.        does not exceed 0.5%.    -   A66. The method of features A64, wherein the amount of total        impurities present following 36 months of storage at 20-25° C.        does not exceed 0.2%.    -   A67. The method of feature A54, wherein the pharmaceutical        composition is an aqueous solution for injection of        phenobarbital or salts thereof.    -   A68. The method of features A67, wherein the aqueous solution is        reconstituted from the lyophilized pharmaceutical composition of        phenobarbital or salts thereof.    -   A69. The method of features A68, wherein the lyophilized        pharmaceutical composition is reconstituted with water for        injection, an aqueous saline or an aqueous dextrose solution.    -   A70. The method of features A67, wherein the aqueous solution is        stable up to 12 hours of storage at 20-25° C.    -   A71. The method of features A70, wherein the amount of total        impurities present following 12 hours of storage at 20-25° C.        does not exceed 0.2%.    -   A72. The method of features A67, wherein the aqueous solution is        stable up to 36 hours of storage at 2-8° C.    -   A73. The method of features A72, wherein the amount of total        impurities present following 36 hours of storage at 2-8° C. does        not exceed 0.2%.    -   A74. The method of features A67, wherein the aqueous solution        has an osmolality below 500 mOsm/kg.    -   A75. The method of feature A54, wherein the pharmaceutical        composition is free of benzyl alcohol.    -   A76. The method of feature A54, wherein the pharmaceutical        composition is free of propylene glycol.    -   A77. A lyophilized pharmaceutical composition of phenobarbital        or salts thereof, wherein the composition has an alcohol content        in the range from about 5000 ppm to about 66000 ppm or        alternatively from about 5000 ppm to about 70000 ppm.    -   A78. The lyophilized pharmaceutical composition of feature A77,        wherein the lyophilized pharmaceutical composition has an        alcohol content in the range from about 12000 ppm to about 66000        ppm.    -   A79. The lyophilized pharmaceutical composition of feature A77,        wherein the lyophilized pharmaceutical composition has an        alcohol content in the range from about 12000 ppm to about 25000        ppm.    -   A80. The lyophilized pharmaceutical composition of features        A77-79, wherein alcohol is a C₁-C₃ alcohol, such as ethanol.    -   A81. The lyophilized pharmaceutical composition of feature A77,        wherein phenobarbital or salts thereof is phenobarbital sodium.    -   A82. The lyophilized pharmaceutical composition of feature A77        is stable up to 36 months of storage at 20-25° C.    -   A83. The lyophilized pharmaceutical composition of feature A82,        wherein the amount of total impurities present following 36        months of storage at 20-25° C. does not exceed 0.5%.    -   A84. The lyophilized pharmaceutical composition of feature A82,        wherein the amount of total impurities present following 36        months of storage at 20-25° C. does not exceed 0.2%.    -   A85. The lyophilized pharmaceutical composition of features        A83-84, wherein the total impurities are selected from        2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,        α-phenylbutyrylguanidine, 2-phenylbutyric acid and        5-methyl-5-phenylbarbituric acid.    -   A86. The lyophilized pharmaceutical composition of feature A77,        wherein the lyophilized pharmaceutical composition is free of        benzyl alcohol.    -   A87. The lyophilized pharmaceutical composition of feature A77,        wherein the lyophilized pharmaceutical composition is free of        propylene glycol.    -   A88. A method for the treatment of neonatal seizure in newborn        infants of 2 weeks of age or younger in need thereof, comprising        administering the lyophilized pharmaceutical composition of        phenobarbital or salts thereof, and wherein the lyophilized        pharmaceutical composition has an alcohol content in the range        from about 5000 ppm to about 66000 ppm or alternatively from        about 5000 ppm to about 70000 ppm.    -   A89. The method of feature A88 comprises reconstituting the        lyophilized pharmaceutical composition of phenobarbital or salts        thereof immediately prior to the administration.    -   A90. The method of feature A89, wherein the lyophilized        pharmaceutical composition is reconstituted with water for        injection, an aqueous saline or an aqueous dextrose solution to        obtain the aqueous solution for injection of phenobarbital or        salts thereof.    -   A91. The method of feature A90, wherein the aqueous solution is        administered intravenously by infusion at a dose of 20 mg/kg        over a course of 15 minutes.    -   A92. The method of features A88 and A89, wherein the method        comprises administering the aqueous solution at an initial        loading dose of 20 mg/kg over a course of 15 minutes and        measuring the electrographic seizures; and if the electrographic        seizures persist or recur after completion of the initial        loading dose, a second dose 20 mg/kg is administered over the        subsequent 15 minutes for a total loading dose of 40 mg/kg.    -   A93. The method of feature A88, wherein the method comprises        administering to neonates in whom correctable abnormalities have        been excluded or corrected.    -   A94. The method of feature A93, wherein the correctable        abnormalities are selected from hypoglycemia or hypocalcemia.    -   A95. The method of feature A88, wherein the lyophilized        pharmaceutical composition has an alcohol content in the range        from about 12000 ppm to about 66000 ppm.    -   A96. The method of feature A88, wherein the lyophilized        pharmaceutical composition has an alcohol content in the range        from about 12000 ppm to about 25000 ppm.    -   A97. The method of features A88, A95-96, wherein alcohol is a        C₁-C₃ alcohol, such as ethanol.    -   A98. The method of feature A88, wherein phenobarbital or salts        thereof is phenobarbital sodium.    -   A99. The method of feature A88, wherein the lyophilized        pharmaceutical composition is stable up to 36 months of storage        at 20-25° C.    -   A100. The method of feature A99, wherein the amount of total        impurities present following 36 months of storage at 20-25° C.        does not exceed 0.5%.    -   A101. The method of feature A99, wherein the amount of total        impurities present following 36 months of storage at 20-25° C.        does not exceed 0.2%.    -   A102. The method of features A100-101, wherein the total        impurities are selected from 2-phenyl-2-ethyl acetyl urea,        2-phenyl-2-ethyl-malonamide, α-phenylbutyrylguanidine,        2-phenylbutyric acid and 5-methyl-5-phenylbarbituric acid.    -   A103. The method of feature A88, wherein the lyophilized        pharmaceutical composition is free of benzyl alcohol.    -   A104. The method of feature A88, wherein the lyophilized        pharmaceutical composition is free of propylene glycol.    -   A105. A pharmaceutical composition of phenobarbital or salts        thereof that has been reconstituted from a lyophilized        pharmaceutical composition of phenobarbital or salts thereof,        wherein the pharmaceutical composition has an alcohol content in        the range from about 5000 ppm to about 66000 ppm or        alternatively from about 5000 ppm to about 70000 ppm.    -   A106. The pharmaceutical composition of feature A105, wherein        the pharmaceutical composition has an alcohol content in the        range from about 12000 ppm to about 66000 ppm.    -   A107. The pharmaceutical composition of feature A105, wherein        the pharmaceutical composition has an alcohol content in the        range from about 12000 ppm to about 25000 ppm.    -   A108. The pharmaceutical composition of feature A105-107,        wherein alcohol is a C₁-C₃ alcohol, such as ethanol.    -   A109. The pharmaceutical composition of feature A105, wherein        phenobarbital or salts thereof is phenobarbital sodium.    -   A110. The pharmaceutical composition of feature A105, wherein        the lyophilized pharmaceutical composition is reconstituted with        water for injection, an aqueous saline or an aqueous dextrose        solution.    -   A111. The pharmaceutical composition of feature A105 is an        aqueous solution for injection of phenobarbital or salts        thereof.    -   A112. The pharmaceutical composition of feature A105, wherein        phenobarbital or salts thereof is present in a concentration of        10-200 mg/ml.    -   A113. The pharmaceutical composition of feature A105, wherein        the pharmaceutical composition is stable up to 12 hours of        storage at 20-25° C.    -   A114. The pharmaceutical composition of feature A113, wherein        the amount of total impurities present following 12 hours of        storage at 20-25° C. does not exceed 0.5%.    -   A115. The pharmaceutical composition of feature A113, wherein        the amount of total impurities present following 12 hours of        storage at 20-25° C. does not exceed 0.2%.    -   A116. The pharmaceutical composition of feature A105, wherein        the pharmaceutical composition is stable up to 36 hours of        storage at 2-8° C.    -   A117. The pharmaceutical composition of feature A116, wherein        the amount of total impurities present following 36 hours of        storage at 2-8° C. does not exceed 0.5%.    -   A118. The pharmaceutical composition of feature A116, wherein        the amount of total impurities present following 36 hours of        storage at 2-8° C. does not exceed 0.2%.    -   A119. The pharmaceutical composition of features A114-115 and        A117-118, wherein the total impurities are selected from        2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,        α-phenylbutyrylguanidine, 2-phenylbutyric acid and        5-methyl-5-phenylbarbituric acid.    -   A120. The pharmaceutical composition of feature A105, wherein        the pharmaceutical composition has an osmolality below 500        mOsm/kg.    -   A121. The pharmaceutical composition of feature A105, wherein        the pharmaceutical composition is free of benzyl alcohol.    -   A122. The pharmaceutical composition of feature AA105, wherein        the pharmaceutical composition is free of propylene glycol.    -   A123. A method for the treatment of neonatal seizure in newborn        infants of 2 weeks of age or younger in need thereof, comprising        administering a pharmaceutical composition of phenobarbital or        salts thereof that has been reconstituted from a lyophilized        pharmaceutical composition of phenobarbital or salts thereof,        and wherein the pharmaceutical composition has an alcohol        content in the range from about 5000 ppm to about 66000 ppm or        alternatively from about 5000 ppm to about 70000 ppm.    -   A124. The method of feature A123, wherein the pharmaceutical        composition is administered intravenously by infusion at a dose        of 20 mg/kg over a course of 15 minutes.    -   A125. The method of feature A123, wherein the method comprises        administering the pharmaceutical composition at an initial        loading dose of 20 mg/kg over a course of 15 minutes and        measuring the electrographic seizures; and if the electrographic        seizures persist or recur after completion of the initial        loading dose, a second dose 20 mg/kg is administered over the        subsequent 15 minutes for a total loading dose of 40 mg/kg.    -   A126. The method of feature A123, wherein the method comprises        administering the pharmaceutical composition to neonates in whom        correctable abnormalities have been excluded or corrected.    -   A127. The method of feature A126, wherein the correctable        abnormalities are selected from hypoglycemia or hypocalcemia.    -   A128. The method of feature A123, wherein the pharmaceutical        composition has an alcohol content in the range from about 12000        ppm to about 66000 ppm.    -   A129. The method of feature A126, wherein the pharmaceutical        composition has an alcohol content in the range from about 12000        ppm to about 25000 ppm.    -   A130. The method of features A123, A128-129, wherein alcohol is        a C₁-C₃ alcohol, such as ethanol.    -   A131. The method of feature A123, wherein phenobarbital or salts        thereof is phenobarbital sodium.    -   A132. The method of feature A123, wherein the lyophilized        pharmaceutical composition is reconstituted with water for        injection, an aqueous saline or an aqueous dextrose solution.    -   A133. The method of feature A123, wherein the pharmaceutical        composition is an aqueous solution for injection of        phenobarbital or salts thereof.    -   A134. The method of feature A123, wherein phenobarbital or salts        thereof is present in a concentration of 10-200 mg/ml.    -   A135. The method of feature A123, wherein the pharmaceutical        composition is stable up to 12 hours of storage at 20-25° C.    -   A136. The method of feature A135, wherein the amount of total        impurities present following 12 hours of storage at 20-25° C.        does not exceed 0.2%.    -   A137. The method of feature A123, wherein the pharmaceutical        composition is stable up to 36 hours of storage at 2-8° C.    -   A138. The method of feature A137, wherein the amount of total        impurities present following 36 hours of storage at 2-8° C. does        not exceed 0.2%.    -   A139. The method of features A136 and A138, wherein the total        impurities are selected from 2-phenyl-2-ethyl acetyl urea,        2-phenyl-2-ethyl-malonamide, α-phenylbutyrylguanidine,        2-phenylbutyric acid and 5-methyl-5-phenylbarbituric acid.    -   A140. The method of feature A123, wherein the pharmaceutical        composition has an osmolality below 500 mOsm/kg.    -   A141. The method of feature A123, wherein the pharmaceutical        composition is free of benzyl alcohol.    -   A142. The method of feature A123, wherein the pharmaceutical        composition is free of propylene glycol.    -   A143. A process of preparing the lyophilized pharmaceutical        composition of phenobarbital or salts thereof having an alcohol        content in the range from about 5000 ppm to about 66000 ppm or        alternatively from about 5000 ppm to about 70000 ppm, wherein        the process comprises dissolving phenobarbital or salts thereof        in water to obtain an aqueous solution of phenobarbital or salts        thereof in a concentration of 10-200 mg/ml and lyophilizing the        aqueous solution to obtain lyophilized pharmaceutical        composition of phenobarbital or salts thereof.    -   A144. The process of feature A143, wherein the process comprises        measuring the alcohol content of the aqueous solution of        phenobarbital or salts thereof and if the alcohol content is        below 5000 ppm then the process further comprises a step of        adding alcohol to achieve the alcohol content of at least about        5000 ppm.    -   A145. The process of features A143, wherein the process        comprises measuring the alcohol content of the lyophilized        pharmaceutical composition of phenobarbital or salts thereof and        if the alcohol content is above 66000 ppm or about 70000 ppm        (whichever is desired), the process further comprises repeating        the lyophilization step multiple times till the alcohol content        of the lyophilized pharmaceutical composition is not more than        about 66000 ppm or about 70000 ppm.    -   A146. The process of feature A143 further comprises addition of        a pH modifier to the aqueous solution of phenobarbital or salts        thereof to achieve a pH in a range of 9-10.5.    -   A147. The process of feature A143, wherein the lyophilized        pharmaceutical composition has an alcohol content in the range        from about 12000 ppm to about 66000 ppm.    -   A148. The process of feature A143, wherein the lyophilized        pharmaceutical composition has an alcohol content in the range        from about 12000 ppm to about 25000 ppm.    -   A149. The process of features A143, A147-148, wherein alcohol is        a C₁-C₃ alcohol, such as ethanol.    -   A150. The process of feature A143, wherein phenobarbital or        salts thereof is phenobarbital sodium.    -   A151. The process of feature A143, wherein the lyophilized        pharmaceutical composition is stable up to 36 months of storage        at 20-25° C.    -   A152. The process of feature A151, wherein the amount of total        impurities present following 36 months of storage at 20-25° C.        does not exceed 0.5%.    -   A153. The process of feature A151, wherein the amount of total        impurities present following 36 months of storage at 20-25° C.        does not exceed 0.2%.    -   A154. The process of features A152-153, wherein the total        impurities are selected from 2-phenyl-2-ethyl acetyl urea,        2-phenyl-2-ethyl-malonamide, α-phenylbutyrylguanidine,        2-phenylbutyric acid and 5-methyl-5-phenylbarbituric acid.    -   A155. The process of feature A143, wherein the lyophilized        pharmaceutical composition is free of benzyl alcohol.    -   A156. The process of feature A143, wherein the lyophilized        pharmaceutical composition is free of propylene glycol.    -   A157. A process of preparing the lyophilized pharmaceutical        composition of phenobarbital or salts thereof having an alcohol        content in the range from about 5000 ppm to about 66000 ppm or        alternatively from about 5000 ppm to about 70000 ppm, the        process comprises dissolving phenobarbital or salts thereof in        water to obtain an aqueous solution having a concentration        10-200 mg/ml; measuring the alcohol content of aqueous solution;        if the alcohol content is below 5000 ppm, adding an alcohol to        achieve the alcohol content of at least about 5000 ppm;        lyophilizing the aqueous solution to obtain lyophilized        pharmaceutical composition; measuring the alcohol content of the        lyophilized pharmaceutical composition; if the alcohol content        is above about 66000 ppm or above about 70000 ppm (whichever is        desired), repeating the lyophilization step multiple times till        the alcohol content of the lyophilized pharmaceutical        composition is not more than about 66000 ppm or about 70000 ppm.    -   A158. The process of feature A157 further comprises addition of        a pH modifier to the aqueous solution of phenobarbital or salts        thereof to achieve a pH in a range of 9-10.5.    -   A159. The process of feature A157, wherein the lyophilized        pharmaceutical composition has an alcohol content in the range        from about 12000 ppm to about 66000 ppm.    -   A160. The process of feature A157, wherein the lyophilized        pharmaceutical composition has an alcohol content in the range        from about 12000 ppm to about 25000 ppm.    -   A161. The process of features A157, A159-160, wherein alcohol is        a C₁-C₃ alcohol, such as ethanol.    -   A162. The process of feature A157, wherein phenobarbital or        salts thereof is phenobarbital sodium.    -   A163. The process of feature A157, wherein the lyophilized        pharmaceutical composition is stable up to 36 months of storage        at 20-25° C.    -   A164. The process of feature A163, wherein the amount of total        impurities present following 36 months of storage at 20-25° C.        does not exceed 0.5%.    -   A165. The process of feature A163, wherein the amount of total        impurities present following 36 months of storage at 20-25° C.        does not exceed 0.2%.    -   A166. The process of features A164-165, wherein the total        impurities are selected from 2-phenyl-2-ethyl acetyl urea,        2-phenyl-2-ethyl-malonamide, α-phenylbutyrylguanidine,        2-phenylbutyric acid and 5-methyl-5-phenylbarbituric acid.    -   A167. The process of feature A157, wherein the lyophilized        pharmaceutical composition is free of benzyl alcohol.    -   A168. The process of feature A157, wherein the lyophilized        pharmaceutical composition is free of propylene glycol.    -   A169. A process of preparing the pharmaceutical composition of        phenobarbital or salts thereof that has been reconstituted from        a lyophilized pharmaceutical composition of phenobarbital or        salts thereof, wherein the pharmaceutical composition has an        alcohol content in the range from about 5000 ppm to about 66000        ppm or alternatively from about 5000 ppm to about 70000 ppm, the        process comprises dissolving phenobarbital or salts thereof in        water to obtain an aqueous solution having a concentration        10-200 mg/ml; lyophilizing the aqueous solution to obtain        lyophilized pharmaceutical composition of phenobarbital or salts        thereof; and reconstituting the lyophilized pharmaceutical        composition to obtain the pharmaceutical composition of        phenobarbital or salts thereof.    -   A170. The process of feature A169, wherein the process comprises        measuring the alcohol content of the aqueous solution of        phenobarbital or salts thereof and if the alcohol content is        below 5000 ppm then the process further comprises a step of        adding alcohol to achieve the alcohol content of at least about        5000 ppm.    -   A171. The process of features A169, wherein said process        comprises measuring the alcohol content of the lyophilized        pharmaceutical composition of phenobarbital or salts thereof and        if the alcohol content is above about 66000 ppm or about 70000        ppm (whichever is desired), the process further comprises        repeating the lyophilization step multiple times till the        alcohol content of the lyophilized pharmaceutical composition is        not more than about 66000 ppm or about 70000 ppm.    -   A172. The process of feature A169 further comprises addition of        pH modifier to the aqueous solution of phenobarbital or salts        thereof to achieve a pH in a range of 9-10.5.    -   A173. The process of feature A169, wherein the lyophilized        pharmaceutical composition is reconstituted with water for        injection, an aqueous saline or an aqueous dextrose solution.    -   A174. The process of feature A169, wherein the pharmaceutical        composition is an aqueous solution for injection of        phenobarbital or salts thereof.    -   A175. The process of feature A169, wherein the pharmaceutical        composition has an alcohol content in the range from about 12000        ppm to about 66000 ppm.    -   A176. The process of feature A169, wherein the pharmaceutical        composition has an alcohol content in the range from about 12000        ppm to about 25000 ppm.    -   A177. The process of feature A169, A175-176, wherein alcohol is        a C₁-C₃ alcohol, such as ethanol.    -   A178. The process of feature A169, wherein phenobarbital or        salts thereof is phenobarbital sodium.    -   A179. The process of feature A169, wherein the pharmaceutical        composition is stable up to 12 hours of storage at 20-25° C.    -   A180. The process of feature A179, wherein the amount of total        impurities present following 12 hours of storage at 20-25° C.        does not exceed 0.2%.    -   A181. The process of feature A169, wherein the pharmaceutical        composition is stable up to 36 hours of storage at 2-8° C.    -   A182. The process of feature A181, wherein the amount of total        impurities present following 36 hours of storage at 2-8° C. does        not exceed 0.2%.    -   A183. The process of features A180 and A182, wherein the total        impurities are selected from 2-phenyl-2-ethyl acetyl urea,        2-phenyl-2-ethyl-malonamide, α-phenylbutyrylguanidine,        2-phenylbutyric acid and 5-methyl-5-phenylbarbituric acid.    -   A184. The process of feature A169, wherein the pharmaceutical        composition has an osmolality below 500 mOsm/kg.    -   A185. The process of feature A169, wherein the pharmaceutical        composition is free of benzyl alcohol.    -   A186. The process of feature A169, wherein the pharmaceutical        composition is free of propylene glycol.    -   A187. A process of preparing the pharmaceutical composition of        phenobarbital or salts thereof that has been reconstituted from        a lyophilized pharmaceutical composition of phenobarbital or        salts thereof, wherein the pharmaceutical composition has an        alcohol content in the range from about 5000 ppm to about 66000        ppm or alternatively from about 5000 ppm to about 70000 ppm,        wherein the process comprises dissolving phenobarbital or salts        thereof in water to obtain an aqueous solution having a        concentration 10-200 mg/ml; measuring the alcohol content of        aqueous solution; if the alcohol content is below 5000 ppm,        adding an alcohol to achieve the alcohol content of at least        about 5000 ppm; lyophilizing the aqueous solution to obtain        lyophilized pharmaceutical composition; measuring the alcohol        content of the lyophilized pharmaceutical composition; if the        alcohol content is above 66000 ppm, repeating the lyophilization        step multiple times till the alcohol content of the lyophilized        pharmaceutical composition is not more than about 66000 ppm or        not more than 70000 ppm (whichever is desired); and        reconstituting the lyophilized pharmaceutical composition to        obtain the pharmaceutical composition of phenobarbital or salts        thereof.    -   A188. The process of feature A187 further comprises addition of        pH modifier to the aqueous solution of phenobarbital or salts        thereof to achieve a pH in a range of 9-10.5.    -   A189. The process of feature A187, wherein the lyophilized        pharmaceutical composition is reconstituted with water for        injection, an aqueous saline or an aqueous dextrose solution.    -   A190. The process of feature A187, wherein the pharmaceutical        composition is an aqueous solution for injection of        phenobarbital or salts thereof.    -   A191. The process of feature A187, wherein the pharmaceutical        composition has an alcohol content in the range from about 12000        ppm to about 66000 ppm.    -   A192. The process of feature A187, wherein the pharmaceutical        composition has an alcohol content in the range from about 12000        ppm to about 25000 ppm.    -   A193. The process of feature A187, A191-192, wherein alcohol is        a C₁-C₃ alcohol, such as ethanol.    -   A194. The process of feature A187, wherein phenobarbital or        salts thereof is phenobarbital sodium.    -   A195. The process of feature A187, wherein the pharmaceutical        composition is stable up to 12 hours of storage at 20-25° C.    -   A196. The process of feature A195, wherein the amount of total        impurities present following 12 hours of storage at 20-25° C.        does not exceed 0.2%.    -   A197. The process of feature A187, wherein the pharmaceutical        composition is stable up to 36 hours of storage at 2-8° C.    -   A198. The process of feature A197, wherein the amount of total        impurities present following 36 hours of storage at 2-8° C. does        not exceed 0.2%.    -   A199. The process of features A196 and A198, wherein the total        impurities are selected from 2-phenyl-2-ethyl acetyl urea,        2-phenyl-2-ethyl-malonamide, α-phenylbutyrylguanidine,        2-phenylbutyric acid and 5-methyl-5-phenylbarbituric acid.    -   A200. The process of feature A187, wherein the pharmaceutical        composition has an osmolality below 500 mOsm/kg.    -   A201. The process of feature A187, wherein the pharmaceutical        composition is free of benzyl alcohol.    -   A202. The process of feature A187, wherein the pharmaceutical        composition is free of propylene glycol.    -   A203. A lyophilized pharmaceutical composition of phenobarbital        or salts thereof having an alcohol content in the range from        about 5000 ppm to about 66000 ppm, wherein the lyophilized        pharmaceutical composition is obtained by a process comprising:        dissolving phenobarbital or salts thereof in water to obtain an        aqueous solution having a concentration 10-200 mg/ml and        lyophilizing the aqueous solution to obtain lyophilized        pharmaceutical composition of phenobarbital or salts thereof.    -   A204. A pharmaceutical composition of phenobarbital or salts        thereof that has been reconstituted from a lyophilized        pharmaceutical composition of phenobarbital or salts thereof        having an alcohol content in the range from about 5000 ppm to        about 66000 ppm, wherein the pharmaceutical composition is        obtained by a process comprising: dissolving phenobarbital or        salts thereof in water to obtain an aqueous solution having a        concentration 10-200 mg/ml; lyophilizing the aqueous solution to        obtain lyophilized pharmaceutical composition of phenobarbital        or salts thereof; and reconstituting the lyophilized        pharmaceutical composition to obtain the pharmaceutical        composition of phenobarbital or salts thereof.    -   A205. A lyophilized pharmaceutical composition comprising        phenobarbital sodium and ethanol, wherein ethanol is present in        an amount sufficient to inhibit degradation of phenobarbital        sodium, such that the amount of total impurities present        following 36 months of storage at 20-25° C. does not exceed        0.2%;        -   wherein the amount of ethanol sufficient to inhibit            degradation of phenobarbital sodium is in the range from            about 12000 ppm to about 25000 ppm;        -   and wherein the pharmaceutical composition is free of benzyl            alcohol and propylene glycol.    -   A206. An aqueous solution for injection comprising phenobarbital        sodium and ethanol, wherein ethanol is present in an amount        sufficient to inhibit degradation of phenobarbital sodium, such        that the amount of total impurities present following 12 hours        of storage at 20-25° C. or following 36 hours of storage at        2-8° C. does not exceed 0.2%;        -   wherein the amount of ethanol sufficient to inhibit            degradation of phenobarbital sodium is in the range from            about 12000 ppm to about 25000 ppm;        -   wherein phenobarbital sodium is present in a concentration            from 10-200 mg/ml;        -   wherein the aqueous solution is reconstituted from the            lyophilized pharmaceutical composition of phenobarbital            sodium;        -   and wherein the aqueous solution is free of benzyl alcohol            and propylene glycol.    -   A207. A process for the preparation of the pharmaceutical        composition of phenobarbital or salts thereof, the process        comprises dissolving phenobarbital or salt thereof in water to        obtain an aqueous solution having a concentration 10-200 mg/ml        and lyophilizing the aqueous solution to obtain lyophilized        pharmaceutical composition, wherein phenobarbital or salts        thereof has an alcohol content in the range from about 5000 ppm        to about 66000 ppm.    -   A208. A lyophilized pharmaceutical composition of phenobarbital        sodium, wherein the composition has an ethanol content in the        range from about 12000 ppm to about 25000 ppm; wherein the        composition is stable up to 36 months of storage at 20-25° C.        such that the amount of total impurities present following 36        months of storage at 20-25° C. does not exceed 0.2%; and wherein        the composition is free of benzyl alcohol and propylene glycol.    -   A209. An aqueous solution for injection of phenobarbital sodium,        wherein the aqueous solution has an ethanol content in the range        from about 12000 ppm to about 25000 ppm; wherein the aqueous        solution is stable up to 12 hours of storage at 20-25° C. or 36        hours of storage at 2-8° C. such that the amount of total        impurities present following 12 hours of storage at 20-25° C. or        following 36 hours of storage at 2-8° C. does not exceed 0.2%;        wherein the aqueous solution is reconstituted from the        lyophilized pharmaceutical composition of phenobarbital sodium;        and wherein the aqueous solution is free of benzyl alcohol and        propylene glycol.

What is claimed is:
 1. A lyophilized pharmaceutical composition ofphenobarbital or salts thereof having an ethanol content in the rangefrom 12000 ppm to 50000 ppm, wherein an amount of total impurities inthe lyophilized pharmaceutical composition does not exceed 0.2%following 36 months of storage at 20-25° C., wherein the lyophilizedpharmaceutical composition is free of benzyl alcohol and propyleneglycol.
 2. The lyophilized pharmaceutical composition of claim 1,wherein the composition has an ethanol content in the range from about12000 ppm to about 25000 ppm.
 3. The lyophilized pharmaceuticalcomposition of claim 1, wherein the phenobarbital or salts thereof isphenobarbital sodium.
 4. The lyophilized pharmaceutical composition ofclaim 1, wherein the total impurities are selected from the groupconsisting of 2-phenyl-2-ethyl acetyl urea, 2-phenyl-2-ethyl-malonamide,α-phenylbutyrylguanidine, 2-phenylbutyric acid and5-methyl-5-phenylbarbituric acid.
 5. A method for the treatment ofneonatal seizure in newborn infants of 2 weeks of age or younger in needthereof, comprising administering the lyophilized pharmaceuticalcomposition of claim
 1. 6. The method of claim 5, wherein the methodcomprises reconstituting the lyophilized pharmaceutical compositionimmediately prior to the administration.
 7. The method of claim 6,wherein the lyophilized pharmaceutical composition is reconstituted withwater for injection, an aqueous saline or an aqueous dextrose solution.8. A lyophilized pharmaceutical composition comprising phenobarbitalsodium having an ethanol content in the range from about 12000 ppm toabout 25000 ppm, wherein an amount of total impurities in thelyophilized pharmaceutical composition does not exceed 0.2% following 36months of storage at 20-25° C., and wherein the pharmaceuticalcomposition is free of benzyl alcohol and propylene glycol.
 9. A methodfor the treatment of neonatal seizure in newborn infants of 2 weeks ofage or younger in need thereof, comprising administering the lyophilizedpharmaceutical composition of claim
 8. 10. The method of claim 9,wherein the method comprises reconstituting the lyophilizedpharmaceutical composition immediately prior to the administration. 11.The method of claim 10, wherein the lyophilized pharmaceuticalcomposition is reconstituted with water for injection, an aqueous salineor an aqueous dextrose solution.
 12. A pharmaceutical composition ofphenobarbital or salts thereof made by a method comprisingreconstituting a lyophilized pharmaceutical composition of thephenobarbital or salts thereof, wherein an amount of total impurities inthe pharmaceutical composition does not exceed 0.2% following 12 hoursof storage at 20-25° C. or 36 hours of storage at 2-8° C., and whereinthe pharmaceutical composition has an ethanol content in a range from12000 ppm to 50000 ppm.
 13. The pharmaceutical composition of claim 12,wherein the ethanol content is in a range of from about 12000 ppm toabout 25000 ppm.
 14. The pharmaceutical composition of claim 12, whereinthe phenobarbital or salts thereof is phenobarbital sodium.
 15. Thepharmaceutical composition of claim 12, wherein the total impurities areselected from the group consisting of 2-phenyl-2-ethyl acetyl urea,2-phenyl-2-ethyl-malonamide, α-phenylbutyrylguanidine, 2-phenylbutyricacid and 5-methyl-5-phenylbarbituric acid.
 16. The pharmaceuticalcomposition of claim 12, wherein the lyophilized pharmaceuticalcomposition is reconstituted with water for injection, an aqueous salineor an aqueous dextrose solution.
 17. The pharmaceutical composition ofclaim 12, wherein the phenobarbital or salts thereof is present in aconcentration of 10-200 mg/ml.
 18. The pharmaceutical composition ofclaim 12, wherein the composition is free of benzyl alcohol andpropylene glycol.
 19. The pharmaceutical composition of claim 12,wherein the pharmaceutical composition has an osmolality below 500mOsm/kg.
 20. A method for the treatment of neonatal seizure in newborninfants of 2 weeks of age or younger in need thereof, comprisingadministering a pharmaceutical composition of claim
 12. 21. Apharmaceutical composition of phenobarbital sodium having an ethanolcontent in the range from about 12000 ppm to about 25000 ppm, whereinthe pharmaceutical composition is made by reconstituting the lyophilizedpharmaceutical composition of phenobarbital sodium; wherein the amountof total impurities present following 12 hours of storage at 20-25° C.or following 36 hours of storage at 2-8° C. does not exceed 0.2%;wherein phenobarbital sodium is present in a concentration from 10-200mg/ml; and wherein the pharmaceutical composition is free of benzylalcohol and propylene glycol.
 22. The pharmaceutical composition ofclaim 21, wherein the lyophilized pharmaceutical composition isreconstituted with water for injection, an aqueous saline or an aqueousdextrose solution.
 23. A method for the treatment of neonatal seizure innewborn infants of 2 weeks of age or younger in need thereof, comprisingadministering a pharmaceutical composition of claim
 21. 24. Thelyophilized pharmaceutical composition of claim 1, wherein thelyophilized pharmaceutical composition comprises HCl.
 25. A lyophilizedpharmaceutical composition of phenobarbital or salts thereof having anethanol content in the range from 12000 ppm to 50000 ppm, wherein anamount of total impurities in the lyophilized pharmaceutical compositiondoes not exceed 0.2% following 36 months of storage at 20° C.-25° C.,wherein, said lyophilized pharmaceutical composition upon reconstitutionwith water for injection or an aqueous saline or an aqueous dextrosesolution provides a stable reconstituted composition up to 12 hours ofstorage at 20° C.-25° C. or 36 hours of storage at 2° C.-8° C.; wherein,an amount of total impurities in the reconstituted composition does notexceed 0.2% following 12 hours of storage at 20° C.-25° C. or 36 hoursof storage at 2° C.-8° C.; wherein said lyophilized pharmaceuticalcomposition and said reconstituted composition are free of benzylalcohol and propylene glycol; optionally wherein said lyophilizedpharmaceutical composition and said reconstituted composition compriseHCl; and wherein said reconstituted composition is suitable for thetreatment of neonatal seizure in newborn infants of 2 weeks of age oryounger in need thereof.